Compositions and methods for treating cns disorders

ABSTRACT

Provided herein is a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or XI: or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/867,618, filed on Jun. 27, 2019, the entire contentof which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization (change ofpotential occurs from −70 mV to −50 mV). This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by γ-aminobutyric acid (GABA), aneurotransmitter. GABA has a profound influence on overall brainexcitability because up to 40% of the neurons in the brain utilize GABAas a neurotransmitter. GABA regulates the excitability of individualneurons by regulating the conductance of chloride ions across theneuronal membrane. GABA interacts with its recognition site on the GRCto facilitate the flow of chloride ions down an electrochemical gradientof the GRC into the cell. An intracellular increase in the levels ofthis anion causes hyperpolarization of the transmembrane potential,rendering the neuron less susceptible to excitatory inputs, i.e.,reduced neuron excitability. In other words, the higher the chloride ionconcentration in the neuron, the lower the brain excitability and levelof arousal.

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains a distinct site for neuroactive steroids. See, e.g., Lan, N. C.et al., Neurochem. Res. (1991) 16:347-356.

Neuroactive steroids can occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

New and improved compounds are needed that act as modulating agents forbrain excitability, as well as agents for the prevention and treatmentof CNS-related diseases. The compounds, compositions, and methodsdescribed herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are compounds designed, for example, to act as GABAmodulators. In some embodiments, such compounds are envisioned to beuseful as therapeutic agents for treating a CNS-related disorder.

In an aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In an aspect, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula II is a compound of FormulaIIIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In an aspect, provided herein is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In an aspect, provided herein is a compound of Formula VIa or VIb:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In an aspect, provided herein is a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In another aspect, provided herein is a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In an aspect, provided herein is a compound of Formula IX:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In an aspect, provided herein is a compound of Formula X:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X).

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula I,II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient. Incertain embodiments, the compound of the present invention is providedin an effective amount in the pharmaceutical composition. In certainembodiments, the compound of the present invention is provided in atherapeutically effective amount.

In one aspect, provided herein is a method of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound described herein or apharmaceutically acceptable salt thereof. In some embodiments, theCNS-related disorder is a sleep disorder, a mood disorder, aschizophrenia spectrum disorder, a convulsive disorder, a disorder ofmemory and/or cognition, a movement disorder, a personality disorder,autism spectrum disorder, pain, traumatic brain injury, a vasculardisease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In some embodiments, the CNS-relateddisorder is depression. In some embodiments, the CNS-related disorder ispostpartum depression. In some embodiments, the CNS-related disorder ismajor depressive disorder. In some embodiments, the major depressivedisorder is moderate major depressive disorder. In some embodiments, themajor depressive disorder is severe major depressive disorder.

In some embodiments, the compound is selected from the group consistingof the compounds identified in Table 1 herein.

Compounds of the present invention as described herein, act, in certainembodiments, as GABA modulators, e.g., effecting the GABA_(A) receptorin either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder. In certain embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In certainembodiments, the compound is administered orally. In certainembodiments, the compound is administered chronically. In certainembodiments, the compound is administered continuously, e.g., bycontinuous intravenous infusion.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention provides compoundsdesigned, for example, to act as GABA_(A) receptor modulators. Incertain embodiments, such compounds are envisioned to be useful astherapeutic agents for treating a CNS-related disorder (e.g., a disorderas described herein, for example depression, such as post-partumdepression or major depressive disorder).

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Isomers, e.g., stereoisomers, can be isolated from mixtures by methodsknown to those skilled in the art, including chiral high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts; or preferred isomers can be prepared by asymmetricsyntheses. See, for example, Jacques et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen et al.,Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds(McGraw-Hill, N Y, 1962); and Wilen, Tables of Resolving Agents andOptical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press,Notre Dame, Ind. 1972). The invention additionally encompasses compoundsdescribed herein as individual isomers substantially free of otherisomers, and alternatively, as mixtures of various isomers.

“Stereoisomers”: It is also to be understood that compounds that havethe same molecular formula but differ in the nature or sequence ofbonding of their atoms or the arrangement of their atoms in space aretermed “isomers.” Isomers that differ in the arrangement of their atomsin space are termed “stereoisomers.” Stereoisomers that are not mirrorimages of one another are termed “diastereomers” and those that arenon-superimposable mirror images of each other are termed “enantiomers.”When a compound has an asymmetric center, for example, it is bonded tofour different groups, a pair of enantiomers is possible. An enantiomercan be characterized by the absolute configuration of its asymmetriccenter and is described by the R- and S-sequencing rules of Cahn andPrelog, or by the manner in which the molecule rotates the plane ofpolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture”.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pureR-position/center/carbon compound can comprise, for example, about 90%excipient and about 10% enantiomerically pure R-compound. In certainembodiments, the enantiomerically pure R-compound in such compositionscan, for example, comprise, at least about 95% by weight R-compound andat most about 5% by weight S-compound, by total weight of the compound.For example, a pharmaceutical composition comprising enantiomericallypure S-compound can comprise, for example, about 90% excipient and about10% enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

The term “diastereomierically pure” denotes that the compound comprisesmore than 75% by weight, more than 80% by weight, more than 85% byweight, more than 90% by weight, more than 91% by weight, more than 92%by weight, more than 93% by weight, more than 94% by weight, more than95% by weight, more than 96% by weight, more than 97% by weight, morethan 98% by weight, more than 98.5% by weight, more than 99% by weight,more than 99.2% by weight, more than 99.5% by weight, more than 99.6% byweight, more than 99.7% by weight, more than 99.8% by weight or morethan 99.9% by weight, of a single diastereomer. Methods for determiningdiastereomeric and enantiomeric purity are well-known in the art.Diastereomeric purity can be determined by any analytical method capableof quantitatively distinguishing between a compound and itsdiastereomers, such as high performance liquid chromatography (HPLC).

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like. When a range or numberof carbons is provided for a particular alkylene group, it is understoodthat the range or number refers to the range or number of carbons in thelinear carbon divalent chain. Alkylene groups may be substituted orunsubstituted with one or more substituents as described herein.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, cyano, hydroxy,C₁₋₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁₋₈ alkyl, C₁₋₈ haloalkyl, 4-10membered heterocyclyl, alkanoyl, C₁₋₈ alkoxy, heteroaryloxy, alkylamino,arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹, COOalkyl,COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl, SOalkyl,SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joined to form acyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionallycontaining one or more heteroatoms selected from the group N, O, or S.R⁶⁰ and R⁶¹ are independently hydrogen, C₁₋₈ alkyl, C₁₋₄ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆₋₁₀ aryl, substitutedC₆₋₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10 memberedheteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁₋₈ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), C(O)—C₁₋₈ alkyl, —C(O)—(CH₂)_(t)(C₆₋₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃₋₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁₋₈ alkyl,substituted with halo or hydroxy; or C₃₋₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆₋₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁₋₄alkyl, halo, unsubstituted C₁₋₄ alkoxy, unsubstituted C₁₋₄ haloalkyl,unsubstituted C₁₋₄ hydroxyalkyl, or unsubstituted C₁₋₄ haloalkoxy orhydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆₋₁₀ aryl, aryloxy, carboxyl,cyano, C₃₋₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆₋₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃₋₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁₋₄ alkyl, halo, unsubstituted C₁₋₄alkoxy, unsubstituted C₁₋₄ haloalkyl, unsubstituted C₁₋₄ hydroxyalkyl,or unsubstituted C₁₋₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Oxo group” refers to —C(═O)—.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstitued alkenyl, substituted or unsubstitued alkynyl,substituted or unsubstitued carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstitued heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃₋₁₀ cycloalkyl; or C₁₋₈ alkyl, substituted with haloor hydroxy; C₃₋₈ alkenyl, substituted with halo or hydroxy; C₃₋₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆₋₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃₋₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁₋₄ alkyl, halo,unsubstituted C₁₋₄ alkoxy, unsubstituted C₁₋₄ haloalkyl, unsubstitutedC₁₋₄ hydroxyalkyl, or unsubstituted C₁₋₄ haloalkoxy or hydroxy; or bothR³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁₋₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆₋₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃₋₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁₋₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁₋₄ alkyl, halo, unsubstituted C₁₋₄alkoxy, unsubstituted C₁₋₄ haloalkyl, unsubstituted C₁₋₄ hydroxyalkyl,or unsubstituted C₁₋₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Haloalkyl” refers to an alkyl radical in which the alkyl group issubstituted with one or more halogens. Typical haloalkyl groups include,but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl,chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl,tetrafluoroethyl, and the like.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa)), —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR)₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃,—OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(cc)(OR),C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups; or two geminal hydrogens on a carbonatom are replaced with the group ═O, ═S, ═NN(R^(bb))₂,═NNR^(bb)C(═O)R^(aa), —NNR^(bb)C(═O)OR^(aa), —NNR^(bb)S(═O)₂R^(aa),—NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(aa) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NRC(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃+X⁻,—N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or twogeminal R^(gg) substituents can be joined to form ═O or ═S; wherein X⁻is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

These and other exemplary substituents are described in more detail inthe Detailed Description, and Claims. The invention is not intended tobe limited in any manner by the above exemplary listing of substituents.

Other Definitions

As used herein, the term “modulation” refers to the inhibition orpotentiation of GABA_(A) receptor function. A “modulator” (e.g., amodulator compound) may be, for example, an agonist, partial agonist,antagonist, or partial antagonist of the GABA_(A) receptor.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977)66(1): 1-79.

The term “prodrug” is intended to encompass therapeutically inactivecompounds that, under physiological conditions, are converted into thetherapeutically active agents of the present invention. One method formaking a prodrug is to design selected moieties that are hydrolyzed orcleaved at a targeted in vivo site of action under physiologicalconditions to reveal the desired molecule which then produces itstherapeutic effect. In certain embodiments, the prodrug is converted byan enzymatic activity of the subject.

In an alternate embodiment, the present invention provides prodrugs ofcompound described herein, wherein the prodrug includes a cleavablemoiety on the C₃ hydroxy as depicted in Formulae depicted herein.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of 7 electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base. Tautomeric forms may berelevant to the attainment of the optimal chemical reactivity andbiological activity of a compound of interest.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human(“human subject”). In certain embodiments, the subject is a non-humananimal.

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn),triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS),t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), andtosylate (Ts).

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

In certain embodiments, the substituent present on a nitrogen atom is anamino protecting group (also referred to herein as a nitrogen protectinggroup). Amino protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)OR^(aa), C(═O)N(R^(cc))₂,—S(═O)₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14-memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14-membered heteroaryl groups, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are as definedherein. Amino protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

Exemplary amino protecting groups include, but are not limited to amidegroups (e.g., —C(═O)R^(aa)), which include, but are not limited to,formamide and acetamide; carbamate groups (e.g., —C(═O)OR^(aa)), whichinclude, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc),t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups(e.g., —S(═O)₂R^(aa)), which include, but are not limited to,p-toluenesulfonamide (Ts), methanesulfonamide (Ms), andN-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition.

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response, e.g., to treat aCNS-related disorder, is sufficient to induce anesthesia or sedation. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound of the invention may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the disease being treated, the mode of administration, andthe age, weight, health, and condition of the subject.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

In an alternate embodiment, the present invention contemplatesadministration of the compounds of the present invention or apharmaceutically acceptable salt or a pharmaceutically acceptablecomposition thereof, as a prophylactic before a subject begins to sufferfrom the specified disease, disorder or condition. As used herein, andunless otherwise specified, a “prophylactically effective amount” of acompound is an amount sufficient to prevent a disease, disorder orcondition, or one or more symptoms associated with the disease, disorderor condition, or prevent its recurrence. A prophylactically effectiveamount of a compound means an amount of a therapeutic agent, alone or incombination with other agents, which provides a prophylactic benefit inthe prevention of the disease, disorder or condition. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

Compounds

It should be appreciated that formulas described herein may referenceparticular carbon atoms, such as C17, C3, C19, etc. These references arebased on the position of carbon atoms according to steroid nomenclatureknown and used in the industry, as shown below:

For example, C17 refers to the carbon at position 17 and C3 refers tothe carbon at position 3.

In one aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof;wherein:

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent;

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl;

n is 0, 1, 2, or 3; and

t is 2 or 3.

In an aspect, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof;wherein:

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent;

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R¹⁵, R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl;

R¹⁸ is substituted or unsubstituted alkyl; and

n is 0, 1, 2, or 3;

provided that when R⁵ is hydrogen, R¹⁸ is not —CH₃.

In some embodiments, the compound of Formula II is a compound of FormulaIIIa or IIIb:

or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of Formula V:

or a pharmaceutically acceptable salt thereof;wherein:

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent;

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R^(15a) or R^(15b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl; and

n is 0, 1, 2, or 3.

In an aspect, provided herein is a compound of Formula VIa or VIb:

or a pharmaceutically acceptable salt thereof;wherein:

-   -   represents a single or double bond, provided if a double bond is        present, then one of R^(6a) or R^(6b) is absent and R⁵ is        absent; R^(X) is selected from the group consisting of halo,        —OH, —OR^(Q1), and substituted or unsubstituted alkyl, wherein        R^(Q1) is substituted or unsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)ORA¹, —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl;

r is 2 or 3;

p is 2 or 3; and

n is 0, 1, 2, or 3.

In an aspect, provided herein is a compound of Formula VII:

or a pharmaceutically acceptable salt thereof;wherein:

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent;

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b), R^(11a),R^(11b), R^(12a), and R^(12b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl; and

n is 0, 1, 2, or 3.

In an aspect, provided herein is a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof;wherein:

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent;

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)ORA¹, —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl;

s is 2; and

n is 0, 1, 2, or 3.

In an aspect, provided herein is a compound of Formula IX:

or a pharmaceutically acceptable salt thereof;wherein:

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)ORA¹, —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl; and

n is 0, 1, 2, or 3.

In another aspect, provided herein is a compound of Formula X:

or a pharmaceutically acceptable salt thereof;wherein:

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent;

R^(X) is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl;

R^(Y) is halo or substituted or unsubstituted alkyl; or

R^(Y) and R^(X) may join together with the intervening atoms to form asubstituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consistingof halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂,—N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA),—N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,—N(R^(GA))S(═O)₂R^(GA), substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocylyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each instance of R^(GA) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocylyl, substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, and a nitrogen protecting group when attached to nitrogen, ortwo R^(GA) groups are taken with the intervening atoms to form asubstituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring;

each of R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, halogen, cyano, —NO₂, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, andsubstituted or unsubstituted alkynyl; or R^(6a) and R^(6b) are joined toform an oxo (═O) group;

each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C3),—N(R^(C3))₂, —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),—C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂,—OC(═O)SR^(C3), —OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),—N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),—SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3), —S(═O)₂OR^(C3), or—S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,an oxygen protecting group when attached to oxygen, a nitrogenprotecting group when attached to nitrogen, and a sulfur protectinggroup when attached to sulfur, or two R^(C3) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclicring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl;

q is 2; and

n is 0, 1, 2, or 3.

Groups R^(1a) and R^(1b)

In some embodiments, each of R^(1a) and R^(1b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1),—C(═O)OR^(A1), or —C(═O)N(R^(A1))₂, wherein each instance of R^(A1) isindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each of R^(1a) and R^(1b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl, or—OR^(A1), wherein each instance of R^(A1) is independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, each of R^(1a) and R^(1b) is independentlyhydrogen, unsubstituted C₁₋₆ alkyl, C₁₋₃ haloalkyl, or —OR^(A1) whereinR^(A1) is hydrogen or unsubstituted alkyl.

In some embodiments, each of R^(1a) and R^(1b) is independently hydrogenor substituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(1a) and R^(1b) is each independently hydrogen.

In some embodiments, R^(1a) and R^(1b) are both hydrogen.

Groups R^(2a) and R^(2b)

In some embodiments each of R^(2a) and R^(2b) is independently hydrogen,halogen, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), or—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In some embodiments, each of R^(2a) and R^(2b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl, or—OR^(A1), wherein each instance of R^(A1) is independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, each R^(2a) and R^(2b) is independently hydrogen,unsubstituted C₁₋₆ alkyl, C₁₋₃ haloalkyl, or —OR^(A1) wherein R^(A1) ishydrogen or unsubstituted alkyl.

In some embodiments, R^(2a) and R^(2b) is each independently hydrogen.

In some embodiments, R^(2a) and R^(2b) are both hydrogen.

Groups R^(4a) and R^(4b)

In some embodiments, R^(4a) and R^(4b) is each independently hydrogen,halogen, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), or—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In some embodiments, each of R^(4a) and R^(4b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl, or—OR^(A1), wherein each instance of R^(A1) is independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, each R^(4a) and R^(4b) is independently hydrogen,unsubstituted C₁₋₆ alkyl, C₁₋₃ haloalkyl, or —OR^(A1) wherein R^(A1) ishydrogen or unsubstituted alkyl.

In some embodiments, R^(4a) and R^(4b) is each independently hydrogen.

In some embodiments, R^(4a) and R^(4b) are both hydrogen.

Groups R^(7a) and R^(7b)

In some embodiments, each of R^(7a) and R^(7b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1),—C(═O)OR^(A1), or —C(═O)N(R^(A1))₂, wherein each instance of R^(A1) isindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each R^(7a) and R^(7b) is independently hydrogen,halogen, cyano, substituted or unsubstituted alkyl, or —OR^(A1), whereineach instance of R^(A1) is independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, or substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each R^(7a) and R^(7b) is independently hydrogen,unsubstituted C₁₋₆ alkyl, C₁₋₃ haloalkyl, or —OR^(A1) wherein R^(A1) ishydrogen or unsubstituted alkyl.

In some embodiments, R^(7a) and R^(7b) is each independently hydrogen.

In some embodiments, R^(7a) and R^(7b) are both hydrogen.

Groups R^(11a) and R^(11b)

In some embodiments, each R^(11a) and R^(11b) is independently hydrogen,halogen, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), or—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, or substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In some embodiments, each R^(11a) and R^(11b) is independently hydrogen,halogen, cyano, substituted or unsubstituted alkyl, or —OR^(A1), whereineach instance of R^(A1) is independently selected from substituted orunsubstituted alkyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each R^(11a) and R^(11b) is independently hydrogen,unsubstituted C₁₋₆ alkyl, C₁₋₃ haloalkyl, or —OR^(A1) wherein R^(A1) isunsubstituted alkyl.

In some embodiments, R^(11a) and R^(11b) is each independently hydrogen.

In some embodiments, R^(11a) and R^(11b) are both hydrogen.

Groups R^(12a) and R^(12b)

In some embodiments, each R^(12a), and R^(12b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1),—C(═O)OR^(A1), or —C(═O)N(R^(A1))₂, wherein each instance of R^(A1) isindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl, orsubstituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, each R^(12a), and R^(12b) is independentlyhydrogen, halogen, cyano, substituted or unsubstituted alkyl, or—OR^(A1), wherein each instance of R^(A1) is independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, each R^(12a) and R^(12b) is independently hydrogen,unsubstituted C₁₋₆ alkyl, C₁₋₃ haloalkyl, or —OR^(A1), wherein R^(A1) ishydrogen or unsubstituted alkyl.

In some embodiments, each R^(12a) and R^(12b) is each independentlyhydrogen.

In some embodiments, R^(12a) and R^(12b) are both hydrogen.

Groups R^(6a) and R^(6b)

In some embodiments, each R^(6a) and R^(6b) is independently hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, or substituted or unsubstituted alkynyl.

In some embodiments, each R^(6a) and R^(6b) is independently hydrogen orsubstituted or unsubstituted alkyl.

In some embodiments, R^(6a) and R^(6b) is each independently hydrogen.

In some embodiments, R^(6a) and R^(6b) are both hydrogen.

Groups R^(15a) and R^(15b)

In some embodiments, each R^(15a) and R^(15b) is independently hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heteroaryl.

In some embodiments, each R^(15a) and R^(15b) is independently hydrogenor substituted or unsubstituted alkyl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogenor unsubstituted alkyl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogenor unsubstituted C₁₋₆alkyl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogenor methyl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogen.

In some embodiments, R^(15a) and R^(15b) are both hydrogen.

Groups R^(16a) and R^(16b)

In some embodiments, each R^(16a) and R^(16b) is independently hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, or substituted or unsubstituted heteroaryl.

In some embodiments, each R^(16a) and R^(16b) is independently hydrogenor substituted or unsubstituted alkyl.

In some embodiments, each R^(16a) and R^(16b) is independently hydrogenor unsubstituted alkyl.

In some embodiments, each R^(16a) and R^(16b) is each independentlyhydrogen.

In some embodiments, R^(16a) and R^(16b) are both hydrogen.

Group R³

In some embodiments, R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, or substituted or unsubstitutedalkynyl.

In some embodiments, R³ is substituted or unsubstituted alkyl.

In some embodiments, R³ is substituted or unsubstituted C₁₋₆alkyl.

In some embodiments, R³ is C₁₋₃ alkyl optionally substituted with C₁₋₃alkoxy.

In some embodiments, R³ is methyl, ethyl, propyl, butyl, —CH₂OCH₃, or—CH₂OCH₂CH₃.

In some embodiments, R₃ is methyl, ethyl, or n-propyl.

In some embodiments, R³ is methyl.

In some embodiments, R³ is ethyl.

In some embodiments, R³ is propyl.

Group R¹⁸

In some embodiments, R¹⁸ is substituted or unsubstituted alkyl.

In some embodiments, R¹⁸ is substituted or unsubstituted C₁₋₆alkyl.

In some embodiments, R¹⁸ is substituted C₁₋₆alkyl.

In some embodiments, R¹⁸ is unsubstituted C₁₋₆alkyl.

In some embodiments, R¹⁸ is methyl.

Group R¹⁹

In some embodiments, R¹⁹ is hydrogen or substituted or unsubstitutedC₁₋₆alkyl.

In some embodiments, R¹⁹ is unsubstituted C₁₋₃alkyl.

In some embodiments, R¹⁹ is hydrogen.

In some embodiments R¹⁹ is —CH₃.

In some embodiments, R¹⁹ is hydrogen or methyl.

Group R^(X) and/or Group R^(Y)

In some embodiments, R^(X) is halo, —OH, —OR^(Q1), or substituted orunsubstituted C₁₋₃alkyl.

In some embodiments, R^(X) is —OH.

In some embodiments, R^(Y) is halo or unsubstituted alkyl.

In some embodiments, R^(Y) is halo or unsubstituted C₁₋₃alkyl.

In some embodiments, R^(Y) is methyl, ethyl, or propyl.

In some embodiments, R^(Y) is methyl.

In some embodiments, R^(X) is —OH and R^(Y) is unsubstituted C₁₋₃alkyl.

In some embodiments, R^(X) is —OH and R is methyl.

In some embodiments, R^(Y) and R^(X) may join together with theintervening atoms to form a substituted or unsubstituted carbocyclicring, or a substituted or unsubstituted heterocyclic ring.

In some embodiments, R^(Y) and R^(X) may join together with theintervening atoms to form a substituted or unsubstituted C₃₋₇carbocyclic ring, or a substituted or unsubstituted C₃₋₇ heterocyclicring.

In some embodiments, R^(Y) and R^(X) join together with the interveningatoms to form a substituted or unsubstituted 4-membered carbocyclicring.

In some embodiments, R^(Y) and R^(X) join together with the interveningatoms to form a substituted or unsubstituted 4-membered heterocyclicring.

In some embodiments, the 4-membered heterocyclic ring contains aheteroatom selected from N, O, and S.

Group R^(Q1)

In some embodiments, R^(Q1) is unsubstituted C₁₋₆alkyl.

In some embodiments, R^(Q1) is methyl.

Group R²²

In some embodiments, R²² is independently for each occurrence hydrogen,halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—N(R^(GA))C(═O)R^(GA), —SR^(GA), —S(═O) R^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocylyl,or substituted or unsubstituted C₃₋₆ heterocylyl; wherein each instanceof R^(GA) is independently hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted C₃₋₆ heterocylyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In some embodiments, R²² is independently for each occurrence halogen,—CN, —OR^(GA), —N(R^(GA))₂, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₃₋₆ carbocylyl; wherein each instance ofR^(GA) is independently hydrogen, substituted or unsubstituted C₁₋₆alkyl, or substituted or unsubstituted C₃₋₆ carbocylyl.

In some embodiments, R²² is independently for each occurrence hydrogen,halogen, —CN, unsubstituted C₁₋₃ alkyl, substituted or unsubstitutedC₃₋₆ heterocylyl, C₁₋₃ haloalkyl, or —OR^(GA), wherein each instance ofR^(GA) is independently hydrogen, substituted or unsubstituted C₁₋₃alkyl.

In some embodiments, R²² is located at the 4-position of the pyrazolyl.

In another embodiment, R²² is located at the 3-position of thepyrazolyl.

In another embodiment, R²² is located at the 5-position of thepyrazolyl.

In some embodiments, R²² is —CN.

In another embodiment, R²² is —CN located at the 4-position of thepyrazolyl.

Integer n

In some embodiments, n is 1 or 2.

In some embodiments, n is 1, 2, or 3.

In some embodiments, n is 0 or 1.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

Integer t

In some embodiments, t is 2. In some embodiments t is 3.

Integer r

In some embodiments, r is 2. In some embodiments r is 3.

Integer p

In some embodiments, p is 2. In some embodiments p is 3.

Integer s

In some embodiments, s is 2.

Integer q

In some embodiments, q is 2.

Group R⁵

In some embodiments, R⁵ is methyl in the alpha or beta configuration.

In some embodiments, R⁵ is methyl in the alpha configuration.

In some embodiments, R⁵ is methyl in the beta configuration.

In some embodiments, R⁵ is a hydrogen in the alpha or betaconfiguration.

In some embodiments, R⁵ is a hydrogen in the alpha configuration.

In some embodiments, R⁵ is a hydrogen in the beta configuration.

In some embodiments, the compound of Formula I is a compound of FormulaI-a:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I is a compound of FormulaI-b:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I is a compound of FormulaI-c or I-d:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VIa or VIb is a compound ofFormula VIa-a or VIb-a:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VIa or VIb is a compound ofFormula VIa-b or VIb-b:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VIa or VIb is a compound ofFormula VIa-c, VIa-d, VIb-c or VIb-d:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VIa or VIb is a compound ofFormula VIa-e or VIb-e.

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VII is a compound ofFormula VII-a:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VII is a compound ofFormula VII-b:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula VII is a compound ofFormula VII-c:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound is selected from the group consistingof the compounds identified in Table 1 below:

TABLE 1 Compound No. STRUCTURE  1

 2

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

30

31

32

33

34

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. In certainembodiments, the compound of the present invention is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the compound of the present invention is provided in atherapeutically effective amount.

Compounds of the present invention as described herein, act, in certainembodiments, as GAB_(A) modulators, e.g., effecting the GABA_(A)receptor in either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in an aspect, provided herein is a method of modulating a GABAAreceptor in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of any one ofclaims described herein or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition described herein.

In another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder. In certain embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In certainembodiments, the compound is administered orally. In certainembodiments, the compound is administered chronically. In certainembodiments, the compound is administered continuously, e.g., bycontinuous intravenous infusion.

Exemplary compounds of the invention may be synthesized from thefollowing known starting materials using methods known to one skilled inthe art or certain references, In one aspect, provided herein is apharmaceutically acceptable salt of a compound described herein (e.g., acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX).

Alternative Embodiments

In an alternative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions. For example, hydrogen maybe ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example,¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, forexample, ¹⁵N, and the like. In other embodiments, a particular isotope(e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least5%, at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of thetotal isotopic abundance of an element that occupies a specific site ofthe compound.

Pharmaceutical Compositions

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula I,II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient. Incertain embodiments, the compound of the present invention is providedin an effective amount in the pharmaceutical composition. In certainembodiments, the compound of the present invention is provided in atherapeutically effective amount.

In certain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 5 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as anointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of the present invention. The acidwhich may be used to prepare the pharmaceutically acceptable salt isthat which forms a non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable excipient, e.g., a composition suitable for injection, suchas for intravenous (IV) administration.

Pharmaceutically acceptable excipients include any and all diluents orother liquid vehicles, dispersion or suspension aids, surface activeagents, isotonic agents, preservatives, lubricants and the like, assuited to the particular dosage form desired, e.g., injection. Generalconsiderations in the formulation and/or manufacture of pharmaceuticalcompositions agents can be found, for example, in Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins,2005).

For example, injectable preparations, such as sterile injectable aqueoussuspensions, can be formulated according to the known art using suitabledispersing or wetting agents and suspending agents. Exemplary excipientsthat can be employed include, but are not limited to, water, sterilesaline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprisesa cyclodextrin derivative. The most common cyclodextrins are α-, β- andγ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units,respectively, optionally comprising one or more substituents on thelinked sugar moieties, which include, but are not limited to,substituted or unsubstituted methylated, hydroxyalkylated, acylated, andsulfoalkylether substitution. In certain embodiments, the cyclodextrinis a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutylether β-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the composition compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, thecomposition comprises hexapropyl-β-cyclodextrin (10-50% in water).

The injectable composition can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,response of the individual patient, the severity of the patient'ssymptoms, and the like.

The compositions are presented in unit dosage forms to facilitateaccurate dosing. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include pre-filled, pre-measured ampules or syringes of theliquid compositions. In such compositions, the compound is usually aminor component (from about 0.1% to about 50% by weight or preferablyfrom about 1% to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

The compounds provided herein can be administered as the sole activeagent, or they can be administered in combination with other activeagents. In one aspect, the present invention provides a combination of acompound of the present invention and another pharmacologically activeagent. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent, and alternating administration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21st ed., Lippincott Williams &Wilkins, 2005.

In one aspect, provided is a kit comprising a composition (e.g., a solidcomposition) comprising a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X.

Combination Therapy

A compound or composition described herein (e.g., a compound of FormulaI, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceuticalsalt thereof, or a composition comprising a compound of Formula I, II,IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceuticallyacceptable salt thereof) may be administered in combination with anadditional agent or therapy. A subject to be administered a compounddisclosed herein may have a disease, disorder, or condition, or asymptom thereof, that would benefit from treatment with another agent ortherapy. Combination therapy may be achieved by administering two ormore agents, each of which is formulated and administered separately, orby administering two or more agents in a single formulation. In someembodiments, the two or more agents in the combination therapy can beadministered simultaneously. In other embodiments, the two or moreagents in the combination therapy are administered separately. Forexample, administration of a first agent (or combination of agents) canprecede administration of a second agent (or combination of agents) byminutes, hours, days, or weeks. Thus, the two or more agents can beadministered within minutes of each other or within 1, 2, 3, 6, 9, 12,15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeksof each other. In some cases even longer intervals are possible. Whilein many cases it is desirable that the two or more agents used in acombination therapy be present in within the patient's body at the sametime, this need not be so.

Combination therapy can also include two or more administrations of oneor more of the agents used in the combination using different sequencingof the component agents. For example, if agent X and agent Y are used ina combination, one could administer them sequentially in any combinationone or more times, e.g., in the order X—Y—X, X—X—Y, Y—X—Y, Y—Y—X,X—X—Y—Y, etc. Exemplary additional agents are described below.

Selective Serotonin Reuptake Inhibitor (SSRI)

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with an SSRI(s). SSRIs include antidepressants that increasethe level of serotonin in the brain. Exemplary SSRIs include, but arenot limited to, Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine(Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), and Sertraline(Zoloft).

Norepinephrine Reuptake Inhibitor (NERI)

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with an NERI(s). Exemplary NERIs include, but are notlimited to, Atomoxetine (Strattera), Reboxetine (Edronax, Vestra),Bupropion (Wellbutrin, Zyban), Duloxetine, Desipramine (Norpramin),Amedalin (UK-3540-1), Daledalin (UK-3557-15), Edivoxetine (LY-2216684),Esreboxetine, Lortalamine (LM-1404), Nisoxetine (LY-94,939), Talopram(tasulopram) (Lu 3-010), Talsupram (Lu 5-005), Tandamine (AY-23,946),and Viloxazine (Vivalan).

Antipsychotics

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with an antipsychotic agent(s). Antipsychotics include D2antagonists, lowering dopaminergic neurotransmission in the dopaminepathways. Exemplary antipsychotics include, but are not limited to,Asenapine (Saphris), Aripiprazole (Abilify), Cariprazine (Vrayar),Clozapine (Clozaril), Droperidol, Fluperlapine, Mesoridazine, QuetiapineHemifumarate, Raclopride, Spiperone, Sulpiride, Trimethobenzamidehydrochloride, Trifluoperazine Dihydrochloride, lurasidone (Latuda),Olanzapine (Zyprexa), Quetiapine (Seroquel), Zotepine, Risperidone(Risperdal), Ziprasidone (Geodon), Mesotidazine, Chlorpromazinehydrochloride, and Haloperidol (Haldol).

Cannabinoids

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with a cannabinoid(s). Exemplary cannabinoids include, butare not limited to, Cannabidiol (Epidiolex), TetrahydrocannabinolicAcid, Tetrahydrocannabinol, Cannabidolic Acid, Cannabinol, Cannabigerol,Cannabichromene, Tetrahydrocannabivarin, and Cannabidivarin.

NMDA Receptor Antagonists

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with an NMDA receptor antagonist(s). NMDA receptorantagonists are a class of drugs that inhibit the action of theN-methyl-d-aspartate receptor. Exemplary NMDA antagonists include, butare not limited to, Ketamine, Esketamine, Ketobemidone, Ifendopril,5,7-Dichlorokynurenic Acid, Licostinel, Memantine, Gavestinel,Phencyclidine, Dextromethorphan, Remacemide, Selfotel, Tiletamine,Dextropropoxyphene, Aptiganel, Dexanabinol, and Amantadine. NMDAreceptor antagonists also include opioids such as Methadone,Dextropropoxyphene, Pethidine, Levorphanol, Tramadol, Neramexane, andKetobemidone.

GABA Receptor Agonists

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with GABA receptor agaonist(s). GABA receptor agonist are aclass of drugs that are agonists for one or more of the GABA receptors.Exemplary GABA receptor agonists include, but are not limited to,Clobazam, Topiramate, Muscimol, Progabide, Riluzole, Baclofen,Gabapentin, Vigabatrin, Valproic Acid, Tiagabine, Lamotrigine,Pregabalin, Phenyloin, Carbamazepine, Thiopental, Thiamylal,Pentobarbital, Secobarbital, Hexobarbital, Butobarbital, Amobarbital,Barbital, Mephobarbital, Phenobarbital, Primidone, Midazolam, Triazolam,Lometazepam, Flutazolam, Nitrazepam, Fluritrazepam, Nimetazepam,Diazepam, Medazepam, Oxazolam, Prazeam, Tofisopam, Rilmazafonoe,Lorazepam, Temazepam, Oxazepam, Fluidazepam, Chlordizaepoxide,Cloxazolam, Flutoprazepam, Alprazolam, Estazolam, Bromazepam,Flurazepam, Clorazepate Potassium, Haloxazolam, Ethyl Loflazepate,Qazepam, Clonazepam, Mexazolam, Etizolam, Brotizolam, Clotizaepam,Propofol, Fospropofol, Zolpidem, Zopiclone, Exzopiclone, Muscimol,TFQP/gaboxadol, Isoguvacine, Kojic amine, GABA, Homotaurine,Homohypotaurine, Trans-aminocyclopentane-3-carboxylic acid,Trans-amino-4-crotonic acid, b-guanidinopropionic acid, homo-b-proline,Isonipecotic acid, 3-((aminoiminomethyl)thio)-2-propenoic acid (ZAP A),Imidazoleacetic acid, and Piperidine-4-sulfonic acid (P4S).

Cholinesterase Inhibitors

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof) is administered incombination with a cholinesterase inhibitor(s). In general, cholinergicsare compounds which mimic the action of acetylcholine and/orbutyrylcholine. Cholinesterase inhibitors are a class of drugs thatprevent the breakdown of acetylcholine. Exemplary cholinesteraseinhibitors include, but are not limited to, Donepizil (Aricept), Tacrine(Cognex), Rivastigmine (Exelon, Exelon Patch), Galantamine (Razadyne,Reminyl), Memantine/Donepezil (Namzaric), Ambenonium (Mytelase),Neostigmine (Bloxiverz), Pyridostigmine (Mestinon Timespan, Regonol),and Galantamine (Razadyne).

The present disclosure also contemplates, among other thingsadministration of a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutical salt thereof, or a compositioncomprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutically acceptable salt thereof) to asubject has been previously administered an agent selected from thegroup consisting of a bronchial muscle/airway relaxant, an antiviral,oxygen, an antibody, and an antibacterial. In some embodiments anadditional agent is administered to a subject prior to administration ofa compound or pharmaceutical composition described herein (e.g., acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutical salt thereof, or a composition comprising a compoundof Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or apharmaceutically acceptable salt thereof) and an additional agent isselected from the group consisting of a bronchial muscle/airwayrelaxant, an antiviral, oxygen, an antibody, and an antibacterial. Insome embodiments, a compound or pharmaceutical composition describedherein (e.g., a compound Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutical salt thereof, or a compositioncomprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutically acceptable salt thereof) isco-administered with to a subject with an agent selected from abronchial muscle/airway relaxant, an antiviral, oxygen, and anantibacterial.

Methods of Use and Treatment

In an aspect, compounds described herein, e.g., compounds of Formula I,II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X are envisioned to beuseful as therapeutic agents for treating a CNS-related disorder (e.g.,sleep disorder, a mood disorder such as depression, a schizophreniaspectrum disorder, a convulsive disorder, epileptogenesis, a disorder ofmemory and/or cognition, a movement disorder, a personality disorder,autism spectrum disorder, pain, traumatic brain injury, a vasculardisease, a substance abuse disorder and/or withdrawal syndrome, ortinnitus) in a subject in need (e.g., a subject with Rett syndrome,Fragile X syndrome, or Angelman syndrome). Exemplary CNS conditionsrelated to GABA-modulation include, but are not limited to, sleepdisorders [e.g., insomnia], mood disorders [e.g., depression depression(e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., milddepression), bipolar disorder (e.g., I and/or II), anxiety disorders(e.g., generalized anxiety disorder (GAD), social anxiety disorder),stress, post-traumatic stress disorder (PTSD), compulsive disorders(e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrumdisorders [e.g., schizophrenia, schizoaffective disorder], convulsivedisorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures],disorders of memory and/or cognition [e.g., attention disorders (e.g.,attention deficit hyperactivity disorder (ADHD)), dementia (e.g.,Alzheimer's type dementia, Lewis body type dementia, vascular typedementia], movement disorders [e.g., Huntington's disease, Parkinson'sdisease], personality disorders [e.g., anti-social personality disorder,obsessive compulsive personality disorder], autism spectrum disorders(ASD) [e.g., autism, monogenetic causes of autism such assynaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelmansyndrome], pain [e.g., neuropathic pain, injury related pain syndromes,acute pain, chronic pain], traumatic brain injury (TBI), vasculardiseases [e.g., stroke, ischemia, vascular malformations], substanceabuse disorders and/or withdrawal syndromes [e.g., addition to opiates,cocaine, and/or alcohol], and tinnitus.

In certain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder.

In an aspect, provided is a method of alleviating or preventing seizureactivity in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention. In some embodiments, the method alleviates or preventsepileptogenesis.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingpremenstrual syndrome (PMS) or postnatal depression (PND) in a subject,comprising administering to the subject in need of such treatment aneffective amount of a compound of the present invention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is depression.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

Inflammation of the central nervous system (CNS) (neuroinflammation) isrecognized to be a feature of all neurological disorders. Majorinflammatory neurological disorders include multiple sclerosis(characterized by an immune-mediated response against myelin proteins),and meningoencephalitis (where infectious agents triggered theinflammatory response). Additional scientific evidence suggests apotential role of inflammatory mechanisms in other neurologicalconditions such as Alzheimer's disease, Parkinson's disease, Huntington'disease, amyotrophic lateral sclerosis, stroke and traumatic braininjuries. In one embodiment, the compounds of the present invention areuseful in treating neuroinflammation. In another embodiment, thecompounds of the present invention are useful in treating inflammationin neurological conditions, including Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, stroke,and traumatic brain injuries.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine Disorders and Dysfunction

Provided herein are methods that can be used for treating neuroendocrinedisorders and dysfunction. As used herein, “neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused byimbalances in the body's hormone production directly related to thebrain. Neuroendocrine disorders involve interactions between the nervoussystem and the endocrine system. Because the hypothalamus and thepituitary gland are two areas of the brain that regulate the productionof hormones, damage to the hypothalamus or pituitary gland, e.g., bytraumatic brain injury, may impact the production of hormones and otherneuroendocrine functions of the brain. In some embodiments, theneuroendocrine disorder or dysfunction is associated with a women'shealth disorder or condition (e.g., a women's health disorder orcondition described herein). In some embodiments, the neuroendocrinedisorder or dysfunction is associated with a women's health disorder orcondition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to,behavioral, emotional, and sleep-related symptoms, symptoms related toreproductive function, and somatic symptoms; including but not limitedto fatigue, poor memory, anxiety, depression, weight gain or loss,emotional lability, lack of concentration, attention difficulties, lossof lipido, infertility, amenorrhea, loss of muscle mass, increased bellybody fat, low blood pressure, reduced heart rate, hair loss, anemia,constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders

The methods described herein can be used for treating neurodegenerativediseases and disorders. The term “neurodegenerative disease” includesdiseases and disorders that are associated with the progressive loss ofstructure or function of neurons, or death of neurons. Neurodegenerativediseases and disorders include, but are not limited to, Alzheimer'sdisease (including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis, and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Mood Disorders

Also provided herein are methods for treating a mood disorder, forexample clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, cataonic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, treatment-resistant depression, refractorydepression, suicidality, suicidal ideation, or suicidal behavior. Insome embodiments, the method described herein provides therapeuticeffect to a subject suffering from depression (e.g., moderate or severedepression). In some embodiments, the mood disorder is associated with adisease or disorder described herein (e.g., neuroendocrine diseases anddisorders, neurodegenerative diseases and disorders (e.g., epilepsy),movement disorders, tremor (e.g., Parkinson's Disease), women's healthdisorders or conditions).

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Peripartum depression refers to depression in pregnancy. Symptomsinclude irritability, crying, feeling restless, trouble sleeping,extreme exhaustion (emotional and/or physical), changes in appetite,difficulty focusing, increased anxiety and/or worry, disconnectedfeeling from baby and/or fetus, and losing interest in formerlypleasurable activities.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during pregnancy. This depression is referredto herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequences. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self-harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or physchological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Post-surgical depression refers to feelings of depression that follow asurgical procedure (e.g., as a result of having to confront one'smortality). For example, individuals may feel sadness or empty moodpersistently, a loss of pleasure or interest in hobbies and activitiesnormally enjoyed, or a persistent felling of worthlessness orhopelessness.

Mood disorder associated with conditions or disorders of women's healthrefers to mood disorders (e.g., depression) associated with (e.g.,resulting from) a condition or disorder of women's health (e.g., asdescribed herein).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

In some embodiments, the method comprises monitoring a subject with aknown depression scale, e.g., the Hamilton Depression (HAM-D) scale, theClinical Global Impression-Improvement Scale (CGI), and theMontgomery-Asberg Depression Rating Scale (MADRS). In some embodiments,a therapeutic effect can be determined by reduction in HamiltonDepression (HAM-D) total score exhibited by the subject. Reduction inthe HAM-D total score can happen within 4, 3, 2, or 1 days; or 96, 84,72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effectcan be assessed across a specified treatment period. For example, thetherapeutic effect can be determined by a decrease from baseline inHAM-D total score after administering a compound described herein, e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or10 months; or 1 year, 2 years, or for life).

In some embodiments, the subject has a mild depressive disorder, e.g.,mild major depressive disorder. In some embodiments, the subject has amoderate depressive disorder, e.g., moderate major depressive disorder.In some embodiments, the subject has a severe depressive disorder, e.g.,severe major depressive disorder. In some embodiments, the subject has avery severe depressive disorder, e.g., very severe major depressivedisorder. In some embodiments, the baseline HAM-D total score of thesubject (i.e., prior to treatment with a compound described herein,e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII,IX, or X) is at least 24. In some embodiments, the baseline HAM-D totalscore of the subject is at least 18. In some embodiments, the baselineHAM-D total score of the subject is between and including 14 and 18. Insome embodiments, the baseline HAM-D total score of the subject isbetween and including 19 and 22. In some embodiments, the HAM-D totalscore of the subject before treatment with a compound described herein,e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII,IX, or X, is greater than or equal to 23. In some embodiments, thebaseline score is at least 10, 15, or 20. In some embodiments, the HAM-Dtotal score of the subject after treatment with a compound describedherein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D totalscore after treatment with a compound described herein, e.g., a compoundof Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is lessthan 10, 7, 5, or 3. In some embodiments, the decrease in HAM-D totalscore is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score at about 0 to10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8)after treatment with a compound described herein, e.g., a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In someembodiments, the decrease in the baseline HAM-D total score to HAM-Dtotal score after treatment with a compound described herein, e.g., acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold). In someembodiments, the percentage decrease in the baseline HAM-D total scoreto HAM-D total score after treatment with a compound described herein,e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII,IX, or X, is at least 50% (e.g., 60%, 70%, 80%, or 90%). In someembodiments, the therapeutic effect is measured as a decrease in theHAM-D total score after treatment with a compound described herein,e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII,IX, or X, relative to the baseline HAM-D total score (e.g., 12, 24, 48hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2days, 14 days, or more) is at least 10, 15, or 20 points.

In some embodiments, the method of treating a depressive disorder, e.g.,major depressive disorder provides a therapeutic effect (e.g., asmeasured by reduction in Hamilton Depression Score (HAM-D)) within 14,10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. Insome embodiments, the method of treating the depressive disorder, e.g.,major depressive disorder, provides a therapeutic effect (e.g., asdetermined by a statistically significant reduction in HAM-D totalscore) within the first or second day of the treatment with a compounddescribed herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X. In some embodiments, the method of treatingthe depressive disorder, e.g., major depressive disorder, provides atherapeutic effect (e.g., as determined by a statistically significantreduction in HAM-D total score) within less than or equal to 14 dayssince the beginning of the treatment with a compound described herein,e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII,IX, or X. In some embodiments, the method of treating the depressivedisorder, e.g., major depressive disorder, provides a therapeutic effect(e.g., as determined by a statistically significant reduction in HAM-Dtotal score) within less than or equal to 21 days since the beginning ofthe treatment with a compound described herein, e.g., a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In someembodiments, the method of treating the depressive disorder, e.g., majordepressive disorder, provides a therapeutic effect (e.g., as determinedby a statistically significant reduction in HAM-D total score) withinless than or equal to 28 days since the beginning of the treatment witha compound described herein, e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, thetherapeutic effect is a decrease from baseline in HAM-D total scoreafter treatment with a compound described herein, e.g., a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X (e.g.,treatment with a compound described herein, e.g., a compound of FormulaI, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, once a day for 14days). In some embodiments, the HAM-D total score of the subject beforetreatment with a compound described herein, e.g., a compound of FormulaI, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 24. Insome embodiments, the HAM-D total score of the subject before treatmentwith a compound described herein, e.g., a compound of Formula I, II,IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 18. In someembodiments, the HAM-D total score of the subject before treatment witha compound described herein, e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, is between and including 14 and18. In some embodiments, the decrease in HAM-D total score aftertreating the subject with a compound described herein, e.g., a compoundof Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, relativeto the baseline HAM-D total score is at least 10. In some embodiments,the decrease in HAM-D total score after treating the subject with acompound described herein, e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, relative to the baseline HAM-Dtotal score is at least 15 (e.g., at least 17). In some embodiments, theHAM-D total score associated with treating the subject with a compounddescribed herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X, is no more than a number ranging from 6 to 8.In some embodiments, the HAM-D total score associated with treating thesubject with a compound described herein, e.g., a compound of Formula I,II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is no more than 7.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Clinical Global Impression-Improvement Scale(CGI)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8hours or less. In some embodiments, the CNS-disorder is a depressivedisorder, e.g., major depressive disorder. In some embodiments, themethod of treating the depressive disorder, e.g., major depressivedisorder provides a therapeutic effect within the second day of thetreatment period. In some embodiments, the therapeutic effect is adecrease from baseline in CGI score at the end of a treatment period(e.g., 14 days after administration).

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Montgomery-Asberg Depression Rating Scale(MADRS)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8hours or less. In some embodiments, the CNS-disorder is a depressivedisorder, e.g., major depressive disorder. In some embodiments, themethod of treating the depressive disorder, e.g., major depressivedisorder provides a therapeutic effect within the second day of thetreatment period. In some embodiments, the therapeutic effect is adecrease from baseline in MADRS score at the end of a treatment period(e.g., 14 days after administration).

A therapeutic effect for major depressive disorder can be determined bya reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scoreexhibited by the subject. For example, the MADRS score can be reducedwithin 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS) isa ten-item diagnostic questionnaire (regarding apparent sadness,reported sadness, inner tension, reduced sleep, reduced appetite,concentration difficulties, lassitude, inability to feel, pessimisticthoughts, and suicidal thoughts) which psychiatrists use to measure theseverity of depressive episodes in patients with mood disorders.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Edinburgh Postnatal Depression Scale (EPDS))within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. In someembodiments, the therapeutic effect is an improvement measured by theEPDS.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Generalized Anxiety Disorder 7-Item Scale(GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety Disorders

Provided herein are methods for treating anxiety disorders (e.g.,generalized anxiety disorder, panic disorder, obsessive compulsivedisorder, phobia, post-traumatic stress disorder). Anxiety disorder is ablanket term covering several different forms of abnormal andpathological fear and anxiety. Current psychiatric diagnostic criteriarecognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Women's Health Disorders

Provided herein are methods for treating conditions or disorders relatedto women's health. Conditions or disorders related to women's healthinclude, but are not limited to, gynecological health and disorders(e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder(PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility andrelated disorders (e.g., polycystic ovary syndrome (PCOS)), otherdisorders and conditions, and issues related to women's overall healthand wellness (e.g., menopause).

Gynecological health and disorders affecting women include menstruationand menstrual irregularities; urinary tract health, including urinaryincontinence and pelvic floor disorders; and such disorders as bacterialvaginosis, vaginitis, uterine fibroids, and vulvodynia.

Premenstrual syndrome (PMS) refers to physical and emotional symptomsthat occur in the one to two weeks before a women's period. Symptomsvary but can include bleeding, mood swings, tender breasts, foodcravings, fatigue, irritability, acne, and depression.

Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Thesymptoms of PMDD are similar to PMS but more severe and may interferewith work, social activity, and relationships. PMDD symptoms includemood swings, depressed mood or feelings of hopelessness, marked anger,increased interpersonal conflicts, tension and anxiety, irritability,decreased interest in usual activities, difficulty concentrating,fatigue, change in appetite, feeling out of control or overwhelmed,sleep problems, physical problems (e.g., bloating, breast tenderness,swelling, headaches, joint or muscle pain).

Pregnancy issues include preconception care and prenatal care, pregnancyloss (miscarriage and stillbirth), preterm labor and premature birth,sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

Miscarriage refers to a pregnancy that ends on its own, within the first20 weeks of gestation.

Abortion refers to the deliberate termination of a pregnancy, which canbe performed during the first 28 weeks of pregnancy.

Infertility and related disorders include uterine fibroids, polycysticovary syndrome, endometriosis, and primary ovarian insufficiency.

Polycystic ovary syndrome (PCOS) refers to an endocrine system disorderamong women of reproductive age. PCOS is a set of symptoms resultingfrom an elevated male hormone in women. Most women with PCOS grow manysmall cysts on their ovaries. Symptoms of PCOS include irregular or nomenstrual periods, heavy periods, excess body and facial hair, acne,pelvic pain, difficulty getting pregnant, and patches of thick, darker,velvety skin. PCOS may be associated with conditions including type 2diabetes, obesity, obstructive sleep apnea, heart disease, mooddisorders, and endometrial cancer.

Other disorders and conditions that affect only women include Turnersyndrome, Rett syndrome, and ovarian and cervical cancers.

Issues related to women's overall health and wellness include violenceagainst women, women with disabilities and their unique challenges,osteoporosis and bone health, and menopause.

Menopause refers to the 12 months after a woman's last menstrual periodand marks the end of menstrual cycles. Menopause typically occurs in awoman's 40s or 50s. Physical symptoms such as hot flashes and emotionalsymptoms of menopause may disrupt sleep, lower energy, or triggeranxiety or feelings of sadness or loss. Menopause includes naturalmenopause and surgical menopause, which is a type of induced menopausedue to an event such as surgery (e.g., hysterectomy, oophorectomy;cancer). It is induced when the ovaries are gravely damaged by, e.g.,radiation, chemotherapy, or other medications.

Epilepsy

The compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX,or X, or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable composition thereof, can be used in a method describedherein, for example in the treatment of a disorder described herein suchas epilepsy, status epilepticus, or seizure.

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

The compounds and methods described herein can be used to treat orprevent epileptogenesis. Epileptogenesis is a gradual process by which anormal brain develops epilepsy (a chronic condition in which seizuresoccur). Epileptogenesis results from neuronal damage precipitated by theinitial insult (e.g., status epilepticus).

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

The compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX,or X or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable composition thereof, can also be administered as aprophylactic to a subject having a CNS disorder e.g., a traumatic braininjury, status epilepticus, e.g., convulsive status epilepticus, e.g.,early status epilepticus, established status epilepticus, refractorystatus epilepticus, super-refractory status epilepticus; non-convulsivestatus epilepticus, e.g., generalized status epilepticus, complexpartial status epilepticus; generalized periodic epileptiformdischarges; and periodic lateralized epileptiform discharges; prior tothe onset of a seizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well-known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures. In some embodiments, the seizure is ageneralized seizure associated with Dravet Syndrome, Lennox-GastautSyndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 FemalePediatric Epilepsy.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, for examplethe compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX,or X can be used to treat cerebellar tremor or intention tremor,dystonic tremor, essential tremor, orthostatic tremor, parkinsoniantremor, physiological tremor, psychogenic tremor, or rubral tremor.Tremor includes hereditary, degenerative, and idiopathic disorders suchas Wilson's disease, Parkinson's disease, and essential tremor,respectively; metabolic diseases (e.g., thyroid-parathyroid-, liverdisease and hypoglycemia); peripheral neuropathies (associated withCharcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regionalpain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic,toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine,alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids,valproate, amiodarone, thyroid hormones, vincristine); and psychogenicdisorders. Clinical tremor can be classified into physiologic tremor,enhanced physiologic tremor, essential tremor syndromes (includingclassical essential tremor, primary orthostatic tremor, and task- andposition-specific tremor), dystonic tremor, parkinsonian tremor,cerebellar tremor, Holmes' tremor (i.e., rubral tremor), palatal tremor,neuropathic tremor, toxic or drug-induced tremor, and psychogenictremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawal,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptoms foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part. Tourette Syndrome is an inheritedneuropsychiatric disorder with onset in childhood, characterized bymultiple motor tics and at least one vocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormality in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Anesthesia/Sedation

Anesthesia is a pharmacologically induced and reversible state ofamnesia, analgesia, loss of responsiveness, loss of skeletal musclereflexes, decreased stress response, or all of these simultaneously.These effects can be obtained from a single drug which alone providesthe correct combination of effects, or occasionally with a combinationof drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achievevery specific combinations of results. Anesthesia allows patients toundergo surgery and other procedures without the distress and pain theywould otherwise experience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

Also described herein are methods of ameliorating one or more symptomsof a respiratory condition in a subject, comprising administering to thesubject an effective amount of a compound or pharmaceutical compositiondescribed herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable saltthereof).

In one aspect, provided herein is a method of treating a subject whereinthe subject exhibits one or more symptoms of a respiratory conditionand/or has been diagnosed with a respiratory condition, comprisingadministering to said subject an effective amount of a compound orpharmaceutical composition described herein (e.g., a compound of FormulaI, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceuticalsalt thereof, or a composition comprising a compound of Formula I, II,IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceuticallyacceptable salt thereof).

In some embodiments, the present disclosure contemplates a method oftreating a subject comprising administering to said subject a compoundor pharmaceutical composition described herein (e.g., a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or apharmaceutically acceptable salt thereof), wherein the subject has arespiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical saltthereof, or a composition comprising a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptablesalt thereof) to a subject exhibiting symptoms of a respiratorycondition, may result in the reduction of the severity of one or moresymptoms of a respiratory condition or retard or slow the progression ofone or more symptoms of a respiratory condition.

In some embodiments, a subject with a respiratory condition has been oris being treated with mechanical ventilation or oxygen. In someembodiments, a subject with a respiratory condition has been or is beingtreated with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutical salt thereof, or a compositioncomprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutically acceptable salt thereof) isadministered to a subject that is being or has been treated withmechanical ventilation. In some embodiments, administration of acompound or pharmaceutical composition described herein (e.g., acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutical salt thereof, or a composition comprising a compoundof Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or apharmaceutically acceptable salt thereof) continues throughout asubject's treatment with mechanical ventilation. In some embodiments,administration of a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutical salt thereof, or a compositioncomprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutically acceptable salt thereof) continuesafter a subject has ended treatment with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutical salt thereof, or a compositioncomprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII,VIII, IX, or X, or a pharmaceutically acceptable salt thereof) isadministered to a subject who is receiving or has received treatmentwith a sedative. In some embodiments, a sedative is propofol or abenzodiazepine.

In some embodiments, the present disclosure includes administering to asubject in need thereof a compound or pharmaceutical compositiondescribed herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa,VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof)in an amount sufficient to increase oxygen saturation in blood. In someembodiments, oxygen saturation in blood is measured using pulseoximetry.

In some embodiments, the present disclosure contemplates a method oftreating a cytokine storm in a patient. In some embodiments a method oftreating a cytokine storm comprising the step of administering to thepatient a compound or pharmaceutical composition described herein (e.g.,a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, orX, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X,or a pharmaceutically acceptable salt thereof). In some embodiments, asymptom of a cytokine storm is lung inflammation. In some embodiments, apatient undergoing a cytokine storm has acute respiratory distresssyndrome (ARDS).

Respiratory Condition

In some embodiments, a subject with a respiratory condition suffers fromrespiratory distress. In some embodiments, respiratory distress includesacute respiratory distress.

In some embodiments, a subject with a respiratory condition may exhibitone or more symptoms selected from the group consisting of airwayhyper-responsiveness, inflammation of lung tissue, lunghypersensitivity, and inflammation-related pulmonary pain.

In some embodiments a subject with a respiratory condition may exhibitinflammation of lung tissue. In some embodiments, inflammation of lungtissue is bronchitis or bronchiectasis. In some embodiments,inflammation of lung tissue is pneumonia. In some embodiments, pneumoniais ventilator-associated pneumonia or hospital-acquired pneumonia. Insome embodiments, pneumonia is ventilator-associated pneumonia.

In some embodiments, administration of the compound or pharmaceuticalcomposition described herein to a subject exhibiting symptoms of arespiratory condition, results in reduction of the severity ofrespiratory distress in a subject with a respiratory condition or retardor slow the progression of respiratory distress in a subject with arespiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical saltthereof, or a composition comprising a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptablesalt thereof) to a subject exhibiting symptoms of a respiratorycondition, results in reduction of the severity of airwayhyper-responsiveness in a subject with a disease associated with acoronavirus or retard or slow the progression of airwayhyper-responsiveness in a subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical saltthereof, or a composition comprising a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptablesalt thereof) to a subject exhibiting symptoms of a respiratorycondition, results in reduction of the severity of inflammation of lungtissue in a subject with a respiratory condition or retard or slow theprogression of inflammation of lung tissue in a subject with arespiratory condition. In some embodiments, administration of a compoundor pharmaceutical composition described herein (e.g., a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or apharmaceutically acceptable salt thereof) to a subject exhibitingsymptoms of a respiratory condition, results in reduction of theseverity of pneumonia in a subject with a respiratory condition orretard or slow the progression of pneumonia in a subject with arespiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical saltthereof, or a composition comprising a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptablesalt thereof) to a subject exhibiting symptoms of a respiratorycondition, results in reduction of the severity of lung hypersensitivityin a subject with a respiratory condition or retard or slow theprogression of lung hypersensitivity in a subject with a respiratorycondition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical saltthereof, or a composition comprising a compound of Formula I, II, IIIa,IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptablesalt thereof) to a subject exhibiting symptoms of a respiratorycondition, results in reduction of the severity of inflammation-relatedpulmonary pain in a subject with a respiratory condition or retard orslow the progression of inflammation-related pulmonary pain in a subjectwith a respiratory condition.

In some embodiments, a subject with a respiratory condition isundergoing or has undergone treatment for an infection, fibrosis, afibrotic episode, chronic obstructive pulmonary disease, Sarcoidosis (orpulmonary sarcoidosis) or asthma/asthma-related inflammation.

In some embodiments, a subject exhibits symptoms of and/or has beendiagnosed with asthma. In some embodiments, a subject is or hasundergone an asthmatic attack.

In some embodiments, a subject is undergoing or has undergone treatmentfor fibrosis or a fibrotic episode. In some embodiments, the fibrosis iscystic fibrosis.

In some embodiments, a respiratory condition is the result of and/orrelated to a disease or condition selected from the group consisting ofcystic fibrosis, asthma, smoke induced COPD, chronic bronchitis,rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency,male infertility caused by congenital bilateral absence of the vasdeferens (CBAVD), mild pulmonary disease, pulmonary sarcoidosis,idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA),liver disease, hereditary emphysema, hereditary hemochromatosis,coagulation-fibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetesmellitus, Laron dwarfism, myleoperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, congenitalhyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia,ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI,Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, progressive supranuclear palsy,Pick's disease, several polyglutamine neurological disorders such asHuntington, spinocerebellar ataxia type I, spinal and bulbar muscularatrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well asspongiform encephalopathies, such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect), Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren'sdisease.

Infections

The present disclosure contemplates, among other things, treatment of asubject who has an infection. The present disclosure contemplates, amongother things, treatment of a subject who has a disease associated withan infection. In some embodiments, an infection is a viral infection ora bacterial infection. In some embodiments, an infection is a viralinfection. In some embodiments, an infection is a bacterial infection.

In some embodiments, a viral infection is an infection of a virusselected from the group consisting of a coronavirus, an influenza virus,human rhinovirus, a human parainfluenza virus, human metapneumovirus anda hantavirus. In some embodiments, a virus is a coronavirus. In someembodiments, a coronavirus is selected from the group consisting ofSARS-CoV, SARS-CoV-2, and MERS-CoV.

The present disclosure contemplates, among other things, treatment of asubject who has a disease associated with coronavirus. In someembodiments, a disease associated with a coronavirus is selected fromthe group consisting of coronavirus disease 2019 (COVID-19), severeacute respiratory syndrome (SARS) and Middle East respiratory syndrome(MERS). In some embodiments, a disease associated with a coronavirus isselected from the group consisting of COVID-19. In some embodiments, acoronavirus is selected from a group consisting of SARS-CoV-1,SARS-CoV-2, and 2012-nCoV. In some embodiments, a coronavirus isSARS-CoV-2.

In some embodiments, a bacterial infection is an infection of a bacteriaselected from the group consisting of Streptococcus pneumoniae,Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, andHaemophilus influenzae. In some embodiments, Staphylococcus aureus ismethicillin-resistant Staphylococcus aureus.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)trituration, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative oxysterols that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

¹H-NMR reported herein (e.g., for the region between δ (ppm) of about0.5 to about 4 ppm) will be understood to be an exemplary interpretationof the NMR spectrum (e.g., exemplary peak integratations) of a compound.

LC-ELSD/MS: (Mobile Phase: 1.5 ML/4 L TFA in water (solvent A) and 0.75ML/4 L TFA in acetonitrile (solvent B), using the elution gradient30%-90% (solvent B) over 0.9 minutes and holding at 90% for 0.6 minutesat a flow rate of 1.2 ml/min; Column: Xtimate C18 2.1*30 mm, 3 um;Wavelength: UV 220 nm; Column temperature: 50° C.; MS ionization: ESI;Detector: PDA & ELSD.

Abbreviations

PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC:pyridinium chlorochromate; TLC: thin layer chromatography; PCC:pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN:9-borabicyclo[3.3.1]nonane; Pd(t-Bu₃P)₂:bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride;i-PrMgCl: Isopropylmagnesium chloride; TBSCl:tert-Butyl(chloro)dimethylsilane; (i-PrO)₄Ti: titaniumtetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl;i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl;BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH:alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS:t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF₃:(Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;Ti(OiPr)₄: tetraisopropoxytitanium; LAH: Lithium Aluminium Hydride; LDA:lithium diisopropylamide; LiOH.H₂O: lithium hydroxide hydrates; MAD:methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN:acetonitrile; NBS: N-bromosuccinimide; Na₂SO₄: sodium sulfate; Na₂S₂O₃:sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc:t-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: Potassiumtri(s-butyl)borohydride; 9-BBNdimer: 9-borabicyclo(3.3.1)nonane(dimer);DIPEA: diisopropylethylamine; DMF: dimethylformamide; FA: formic acid;SM: starting material.

Example 1 & 2: Synthesis of1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile&1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile

Synthesis of 1.2

To the solution of (5α)-Estrane-3,17-dione, 1.1 (20 g, 72.8 mmol) in THF(200 mL) was added n-PrMgCl (109 mL, 218 mmol, 2M in THF) dropwise at−60° C. After stirring at −60° C. for 2 h, the reaction mixture waspoured into saturated aqueous NH₄Cl (400 mL) at 0° C. and extracted withEtOAc (2×200 mL). The combined organic layer was dried over Na₂SO₄,filtered, concentrated and purified by silica gel column(PE/EtOAc=0-20%) to give 1.2 (18.4 g) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.43 (dd, J=8.8, 19.3 Hz, 1H), 2.16-2.00 (m, 1H), 1.97-1.85(m, 2H), 1.83-1.72 (m, 3H), 1.68-1.43 (m, 5H), 1.40-0.89 (m, 17H), 0.87(s, 3H), 0.79-0.61 (m, 2H).

Synthesis of 1.3

To a solution of di-isopropylamine (19.4 mL, 0.718 g/mL, 139 mmol) inTHF (64 mL) was added n-butyl-lithium (55.6 mL 2.5 M in hexane, 139mmol) at −78° C. After stirring at −78° C. for 10 min, the LDA solutionwas added to a solution of 1.2 (11.7 g, 36.7 mmol) and ethyldiazoacetate (20.8 g, 183 mmol) in THF (400 mL) at −78° C. Afterstirring at −78° C. for 2 h, the reaction was quenched with acetic acid(10.9 g, 183 mmol) in THF (50 mL), stirred at 15° C. for 16 h, pouredinto water (1000 mL) and extracted with EtOAc (3×500 mL). The combinedorganic layers were washed with brine (1500 mL), dried over anhydrousNa₂SO₄, filtered and evaporated under reduced pressure to give 1.3 (20g) as an oil, which was used as is.

Synthesis of 1.4

To a solution of 1.3 (20 g) and DME (200 mL) was added Rh₂(OAc)₄ (204mg, 0.462 mmol) in one portion at 15° C. After stirring at 15° C. for 2h, the reaction mixture was concentrated to give 1.4 (20 g) as an oil,which was used as is.

Synthesis of 1.5

To a solution of 1.4 (20 g) in MeOH (200 mL) was added KOH (27.7 g, 494mmol) at 15° C. After heating at 70° C. for 1 h, the reaction mixturewas poured into H₂O (200 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layer was washed with HCl (1M, 100 mL), saturatedNaHCO₃ (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by flash-combi (0-15% ofEtOAc in PE) to give 1.5 (4.0 g) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H) 2.62 (dt, J=6.8, 14.1 Hz, 1H), 2.19 (br d, J=10.3 Hz, 1H), 2.05(dt, J=2.6, 6.6 Hz, 1H), 1.93-1.57 (m, 8H), 1.54-1.12 (m, 12H),1.12-1.05 (m, 4H), 1.05-0.84 (m, 7H), 0.65 (br dd, J=2.8, 10.8 Hz, 2H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₂H₃₅O [M−H₂O+H]⁺ 315.2 found315.2.

Synthesis of 1.6

To a suspension of Ph₃PEtBr (10.6 g, 28.8 mmol) in anhydrous THF (50 mL)was added t-BuOK (4.84 g, 43.2 mmol) at 15° C. under N₂. After stirringat 45° C. for 30 min, a solution of 1.5 (4.8 g, 14.4 mmol) in anhydrousTHF (50 mL) was dropwise. After stirring for 16 h at 45° C., thereaction mixture was cooled, poured into ice-water (100 mL), stirred for10 min, and extracted with EtOAc (2×100 mL). The combine organic phasewas washed with saturated brine (2×200 mL), filtered and concentrated.The residue was purified by flash column (0˜10% of EtOAc in PE) to give1.6 (1.8 g, 36.2%) as a solid and recovered starting material 1.5 (1.2g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.15 (br t, J=6.5 Hz, 1H),2.50 (br d, J=13.8 Hz, 1H), 2.25-2.06 (m, 1H), 2.02-1.59 (m, 9H),1.41-1.02 (m, 14H), 0.95-0.61 (m, 4H).

Synthesis of 1.7

To a solution of 1.6 (1.8 g, 5.22 mmol) in THF (50 ml) was added 9-BBNdimer (3.80 g, 15.6 mmol) at 15° C. After stirring at 50° C. for 16 h,the reaction mixture was cooled and diluted sequentially with EtOH (6.05ml, 104 mmol, 0.789 g/ml) at 0° C., NaOH (20.8 mL, 5M, 104 mmol)dropwise and H₂O₂ (11.7 g, 104 mmol, 30% in water) dropwise maintaininginner temperature below 30° C. After stirring at 50° C. for 1 h, thereaction mixture was quenched with saturated aqueous Na₂S₂O₃ (130 mL).After stirring at 0° C. for another 1 h, the reaction was checked bypotassium iodide-starch test paper to confirm excess H₂O₂ was destroyed.The aqueous phase was extracted with DCM (3×50 mL). The combine organicphase was washed with saturated Na₂S₂O₃ (2×100 mL), brine (2×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give 1.7 (800 mg) as a solid.

Synthesis of 1.8

To a solution of 1.7 (800 mg, 2.20 mmol) in DCM (30 mL) was added DMP(1.86 g, 4.40 mmol) at 25° C. After stirring at 25° C. for 1 h, themixture was diluted with NaHCO₃ (50 mL) and Na₂S₂O₃ (50 mL, sat.) andextracted with DCM (2×50 mL). The combined organic phase was washed withNaHCO₃ (100 mL), Na₂S₂O₃ (100 mL, sat.) and brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrate, dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash column (0-15% ofEtOAc in PE) to give 1.8 (740 mg) as an oil. ¹H NMR (400 MHz, CDCl₃)δ_(H) 2.32 (dd, J=3.3, 12.5 Hz, 1H), 2.18-2.13 (m, 4H), 1.92-1.66 (m,9H), 1.46-1.20 (m, 12H), 1.11-0.67 (m, 14H).

Synthesis of 1.8a & 1.8b

To a solution of 1.8 (5.8 g, 16.0 mmol) in MeOH (100 mL) at 0° C. wasadded MeONa (12.9 g, 240 mmol). After stirring at 70° C. for 16 h, thereaction mixture was added to saturated NH₄Cl (100 mL) and extractedwith EtOAc (2×100 mL). The combined organic phase was washed withsaturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue (200 mg) was purified by column (0-3% ofacetone in DCM) to give 1.8a (69.3 mg, 34.8%) and 1.8b (16.0 mg, 8.04%)both as solids.

1.8a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.30 (dd, J=3.3, 12.8 Hz, 1H), 2.14(s, 3H), 1.86-1.59 (m, 8H), 1.51-1.21 (m, 9H), 1.15-0.89 (m, 14H),0.87-0.50 (m, 5H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₄H₃₉O[M−H₂O+H]⁺ 343.3 found 343.3.

1.8b: ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.47 (d, J=5.9 Hz, 1H), 2.12 (s,3H), 1.74 (br d, J=12.5 Hz, 7H), 1.51-1.19 (m, 12H), 1.16-0.74 (m, 16H),0.68-0.51 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₄H₃₉O[M−H₂O+H]⁺ 343.3 found 343.3.

Synthesis of 1.9

To a suspension of MePh₃PBr (4.31 g, 12.2 mmol) in anhydrous THF (20 mL)was added t-BuOK (1.36 g, 12.2 mmol) at 15° C. under N₂. After stirringat 40° C. for 30 min, a solution of 1.8a (2.2 g, 6.10 mmol) in anhydrousTHF (20 mL) was dropwise. After stirring for 16 h at 40° C., the mixturewas cooled, poured into ice-water (150 mL), stirred for 10 min, andextracted with EtOAc (2×100 mL). The combine organic phase was washedwith saturated brine (2×100 mL), filtered and concentrated. The residuewas purified by flash column (0˜10% of EtOAc in PE) to give 1.9 (1.9 g,87.1%) as a solid. ¹H NMR (400 MHz, CDCl3) δH 4.80 (s, 1H), 4.61 (d,J=2.0 Hz, 1H), 1.76 (br s, 4H), 1.73-1.47 (m, 11H), 1.37-1.18 (m, 7H),1.13-0.84 (m, 12H), 0.83 (s, 3H), 0.81-0.53 (m, 3H).

Synthesis of 1.10

To a solution of 1.9 (700 mg, 1.95 mmol) in DCM (10 mL) was added m-CPBA(790 Mg, 85%, 3.90 mmol) at 0° C. After stirring at 25° C. for 1 h, themixture was quenched with NaHCO₃ (50 mL, sat. aq.) and Na₂S₂O₃ (20 mL,sat. aq.). The organic layer was separated, dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash column (0˜10% ofEtOAc in PE) to give 1.10 (340 mg, 46.5%) as a solid. ¹H NMR (400 MHz,CDCl3) δH 2.77-2.55 (m, 2H), 1.82-1.65 (m, 8H), 1.54-1.47 (m, 2H),1.47-1.25 (m, 8H), 1.06-0.88 (m, 16H), 0.84-0.56 (m, 5H), 0.55-0.54 (m,1H).

Synthesis of 1 & 2

To a solution of 1.10 (340 mg, 0.908 mmol) in DMF (10 mL) were added1H-pyrazole-4-carbonitrile (168 mg, 1.81 mmol) and Cs₂CO₃ (593 mg, 1.81mmol) at 20° C. After stirring at 120° C. for 2 h, the mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was concentrated and purified by flash column(30˜50% EtOAc in PE) to give mixture of diastereomers of 1 & 2 (350 mg)as a solid. The diastereomers were separated by SFC (Column DAICELCHIRALCEL OD-H (250 mm*30 mm, 5 um) Condition 0.1% NH₃H₂O EtOH Begin B30% End B 30% Gradient Time (min) 100% B Hold Time (min) FlowRate(ml/min) 50) to afford 2 (208.9 mg) and 1 (50.2 mg) both as solids.

1: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.83 (s, 1H), 4.27 (d,J=14.0 Hz, 1H), 4.00 (d, J=13.9 Hz, 1H), 3.00 (s, 1H), 2.36 (br d,J=12.8 Hz, 1H), 1.95-1.56 (m, 5H), 1.42-1.35 (m, 6H), 1.28-1.22 (m, 3H),1.18 (s, 3H), 1.15-1.05 (m, 5H), 1.01 (s, 3H), 0.95-0.88 (m, 8H),0.88-0.56 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₂N₃[M−2H₂O+H]⁺ 432.4 found 432.4.

2: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.79 (s, 1H), 4.52-4.13(m, 2H), 2.47 (br s, 1H), 2.30 (br d, J=13.0 Hz, 1H), 1.91-1.68 (m, 7H),1.45-1.20 (m, 12H), 1.15-1.03 (m, 2H), 1.00-0.70 (m, 17H), 0.66-0.53 (m,1H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₂N₃ [M−2H₂O+H]⁺ 432.3found 432.3.

Example 6 & 7: Synthesis of1-((R)-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile&1-((S)-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile

Synthesis of 6.2

To a solution of BHT (144 g, 654 mmol) in toluene (165 mL) undernitrogen at 0° C. was added AlMe₃ (2 M in toluene, 163 mL, 327 mmol)dropwise. After stirring at 25° C. for 1 h, the MAD solution was usedwithout further purification. To the MAD (327 mmol) solution was added asolution of (5β)-estrane-3,17-dione, 6.1 (30 g, 109 mmol) in DCM (100mL) dropwise at −70° C. After stirring at −70° C. for 1 h under N₂,EtMgBr (130 mL, 327 mmol, 2.5 M in ethyl ether) was added dropwise at−70° C. After stirring at −70° C. for another 2 h, the reaction mixturewas poured into saturated aqueous citric acid (100 mL) at 10° C. andextracted with DCM (2×40 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (PE/EtOAc=0-20%) to afford 6.2 (25 g, 76%) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.50-2.36 (m, 1H), 2.14-2.01 (m,1H), 1.97-1.88 (m, 1H), 1.84-1.74 (m, 4H), 1.68-1.45 (m, 7H), 1.43-0.97(m, 12H), 0.92-0.82 (m, 6H).

Synthesis of 6.3

To a solution of DIPA (34.7 g, 343 mmol) in THF (190 mL) was added BuLi(124 mL, 2.5 M in hexane, 312 mmol) at −70° C. After warming to 0° C.and stirring for 1 h. The cold (−70° C.) LDA solution (312 mL, 1.0 M,312 mmol) was added to a stirred solution of 6.2 (19 g, 62.4 mmol) andethyl diazoacetate (35.5 g, 312 mmol) in THF (100 mL) at −78° C. Afterstirring at −70° C. for 1 h, the reaction mixture was quenched withacetic acid (18.7 g, 312 mmol) in THF (50 mL), warmed to 20° C., dilutedwith water (300 mL) and extracted with EtOAc (3×400 mL). The combinedorganic layers were washed with brine, dried by Na₂SO₄, and evaporatedunder reduced pressure. The residue was purified by flash column (0-5%of EtOAc in PE) to give 6.3 (6 g) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H) 4.80 (m, 1H), 4.33-4.19 (m, 2H), 2.20-2.08 (m, 1H), 1.93-1.54 (m,9H), 1.50-1.28 (m, 12H), 1.19-0.98 (m, 5H), 0.95-0.81 (m, 6H).

Synthesis of 6.4

To a solution of 6.3 (6.0 g, 14.3 mmol) in DME (30 mL) was addedRh₂(OAc)₄ (94.7 mg, 0.2 mmol) at 25° C. After stirring at 25° C. for 12h, the reaction mixture was concentrated to afford 6.4 (6 g) as a solid,which was used as is.

Synthesis of 6.5

To a mixture of 6.4 (6.00 g, 15.3 mmol) in MeOH/THF (30 mL/30 mL) wasadded KOH (8.58 g, 153 mmol). After stirring at 70° C. for 12 h, thereaction mixture was extracted with ethyl acetate (4×80 mL). Thecombined organic phase was washed with water (80 mL), brine (50 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column (15˜30% EtOAc in PE) to give 6.5(3.9 g, 80%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.69-2.53 (m,1H), 2.23-2.14 (m, 1H), 2.08-1.99 (m, 1H), 1.87-1.58 (m, 10H), 1.54-1.21(m, 12H), 1.19-0.93 (s, 6H), 0.90-0.79 (m, 3H).

Synthesis of 6.6

To a suspension of Ph₃PEtBr (13.5 g, 36.5 mmol) in anhydrous THF (100mL) was added t-BuOK (5.47 g, 48.8 mmol) at 15° C. under N₂. Afterstirring at 40° C. for 30 min, a solution of 6.5 (3.9 g, 12.2 mmol) inanhydrous THF (50 mL) was added dropwise. After stirring for 16 h, themixture was cooled, poured into ice-water (150 mL), stirred for 10 minand extracted with EtOAc (2×100 mL). The combine organic phase waswashed with saturated brine (2×200 mL), filtered and concentrated. Theresidue was purified by flash column (10%-30% Ethyl ether in PE) to give6.6 (3.1 g, 77%) a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.52-5.09 (m,1H), 2.30-2.09 (m, 1H), 1.89-1.57 (m, 14H), 1.51-1.19 (m, 10H),1.12-1.02 (m, 3H), 1.00-0.83 (m, 8H).

Synthesis of 6.7

To a solution of 6.6 (3.1 g, 9.4 mmol) in THF (10 ml) was added BH₃.Me₂S(2.81 mL, 28.1 mmol) at 0° C. After stirring at 15° C. for 12 h, thereaction mixture was cooled and quenched sequentially with EtOH (5.46ml, 93.7 mmol, 0.789 g/ml) at 0° C. and NaOH (18.7 mL, 5M, 93.7 mmol).H₂O₂ (9.38 mL, 93.7 mmol, 1.13 g/mL, 30% in water) was then added slowlyuntil the inner temperature no longer rises and the inner temperaturewas maintained below 30° C. After stirring at 50° C. for another 1 h,the reaction mixture was quenched with saturated aqueous Na₂S₂O₃ (50mL), stirred at 0° C. for 1 h, and extracted with DCM (3×50 mL). Thecombine organic phase was washed with saturated Na₂S₂O₃ (2×50 mL), brine(2×50 mL), dried over anhydrous Na₂SO₄ filtered and concentrated to give6.7 (3.26 g) as a solid, which was used as is.

Synthesis of 6.8

To a mixture of 6.7 (3.26 g, 9.35 mmol) and silica gel (5 g) in DCM (15mL) was added PCC (3.01 g, 14.0 mmol) in portions. After stirring at 15°C. for 1 h, the reaction mixture was filtered, and the filtrate wasconcentrated to give 6.8 (3.24 g) as an oil.

Synthesis of 6.8a

To a solution of 6.8 (2 g, 5.8 mmol) in MeOH (20 mL) at 0° C. was addedMeONa (4.67 g, 86.5 mmol). After stirring at 70° C. for 16 h, thereaction mixture was added saturated NH₄Cl (20 mL) and extracted withEtOAc (2×20 mL). The combined organic phase was washed with saturatedbrine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by flash column (0-20% of EtOAc in PE) to give6.8a (1.5 g) as a solid.

Synthesis of 6.9

To a mixture of MePPh₃Br (3.07 g, 8.63 mmol) in THF (12 mL) was addedt-BuOK (966 mg, 8.63 mmol) at 15° C. under N₂. After stirring at 50° C.for 30 min, 6.8a (1 g, 2.88 mmol) in THF (8 mL) was added in portionsbelow 50° C. After stirring at 50° C. for 1 h, the reaction mixture wasquenched with 10% NH₄Cl aqueous (30 mL) at 15° C. and extracted withEtOAc (2×30 mL). The combined organic phase was concentrated underreduced pressure. The residue was purified by silica gel chromatography(EtOAc/PE=0 to 15%) to give 6.9 (720 mg, 72.5%) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H) 4.80 (s, 1H), 4.62-4.58 (m, 1H), 1.86-1.58 (m, 5H),1.57-1.50 (m, 6H), 1.49-1.39 (m, 3H), 1.38-1.23 (m, 6H), 1.22-1.15 (m,2H), 1.14-0.85 (m, 10H), 0.84-0.83 (m, 3H), 0.82 (s, 3H).

Synthesis of 6.10

To a solution of 6.9 (720 mg, 2.08 mmol) in DCM (5 mL) was added m-CPBA(893 mg, 4.16 mmol, 80%) at 15° C. After stirring at 15° C. for 1 h, themixture was quenched with sat. NaHCO₃ and Na₂S₂O₃ (10 mL, v:v=1:1) andextracted with DCM (2×10 mL). The combined organic phase was washed withsat. NaHCO₃ and Na₂S₂O₃ (10 mL, v:v=1:1), dried over Na₂SO₄, filteredand concentrated to give 6.10 (900 mg) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)8.07-8.04 (m, 1H), 8.03-7.95 (m, 1H), 7.66-7.52 (m, 1H),7.50-7.35 (m, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 2.70-2.60(m, 2H), 1.85-1.65 (m, 6H), 1.64-1.50 (m, 6H), 1.49-1.26 (m, 4H),1.25-2.60 (m, 5H), 1.20-0.85 (m, 10H).

Synthesis of 6 &7

To a solution of 6.10 (900 mg, 2.49 mmol) in DMF (5 mL) were addedCs₂CO₃ (2.43 g, 7.47 mmol) and 1H-pyrazole-4-carbonitrile (579 mg, 6.22mmol). After stirring at 130° C. for 12 h, the mixture was added intosaturated NH₄Cl (10 mL) and extracted with EtOAc (3×10 mL). The combinedorganic layer was washed with LiCl (10 mL, 5% in water), saturated brine(2×10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated toafford a mixture of diastereomers 6 & 7 (670 mg) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H) 7.98 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 4.25-4.211(m, 2H), 2.50 (m, 2H), 2.38-2.30 (m, 1H), 2.05 (s, 3H), 1.73-1.60 (m,6H), 1.59-1.52 (m, 5H), 1.51-1.47 (m, 5H), 1.46-1.24 (m, 3H), 1.23 (s,1H), 1.00-0.88 (m, 6H), 0.87-0.85 (m, 6H).

The diastereomers (670 mg) was were separated by SFC (DAICEL CHIRALCELOJ-H (250 mm*30 mm, 5 um), Condition: 0.1% NH₃H₂O EtOH, Begin B: 25%,End B: 25%, FlowRate (ml/min):60) to afford 6 (212.6 mg, 31.8%) and 7(55 mg) as solids. 7 was further purified by SFC (Column: DAICELCHIRALCEL OJ-H (250 mm*30 mm, 5 um), Condition: 0.1% NH₃H₂O EtOH, BeginB: 25%, End B: 25%, FlowRate (ml/min):60) to afford 7 (33.5 mg) as asolid.

6: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.80 (s, 1H), 4.39-4.20(m, 2H), 2.45-2.25 (m, 2H), 1.74-1.62 (m, 7H), 1.61-1.55 (m, 6H),1.54-1.48 (m, 7H), 1.47-1.35 (m, 6H), 1.35-1.25 (m, 4H), 1.05-0.95 (m,4H), 0.90-0.85 (m, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₈H₄₀N₃ [M−2H₂O+H]⁺ 418 found 418. SFC 99% de.

7: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.86 (s, 1H), 4.30-4.24(m, 1H), 4.01-3.95 (m, 1H), 3.05 (s, 1H), 2.42-2.38 (m, 1H), 1.84-1.74(m, 2H), 1.73-1.45 (m, 9H), 1.44-1.19 (m, 11H), 1.18-1.00 (m, 6H),0.99-0.86 (m, 9H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄₀N₃[M−2H₂O+H]⁺ 418 found 418. SFC 100% de.

Example 8 & 9: Synthesis of1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile&1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile

Synthesis of 8.2

To a solution of BHT (96 g, 436 mmol) in toluene (300 mL) under nitrogenat 0° C. was added AlMe₃ (2 M in toluene, 109 mL, 218 mmol) dropwise.After stirring at 25° C. for 1 h, the MAD solution was used directlywithout further purification. To the fresh prepared MAD (218 mmol)solution was added a solution of 6.1 (20 g, 72.8 mmol) in DCM (80 mL)dropwise at −70° C. After stirring at −70° C. for 1 h under N₂, n-PrMgCl(72.5 mL, 145 mmol, 2 M in ethyl ether) was added dropwise at −70° C.After stirring at −70° C. for 2 h, the reaction mixture was poured intosaturated aqueous citric acid (1000 mL) at 10° C. and extracted withEtOAc (2×400 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0˜20% of EtOAc in PE) to afford 8.2 (12 g, 52%) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H) 2.44 (dd, J=8.5, 19.3 Hz, 1H), 2.15-2.07 (m, 1H),2.13-2.00 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.59 (m, 6H), 1.54-1.00 (m,18H), 0.93 (t, J=7.2 Hz, 3H), 0.87 (s, 3H).

Synthesis of 8.3

To a solution of 8.2 (12.0 g, 37.6 mmol) and ethyl diazoacetate (19.7mL, 188 mmol, 1.085 g/mL) in THF (800 mL) was added freshly prepared LDA(180 mL, 1.0 M, 180 mmol) at −78° C. After stirring at −78° C. for 2 h,the reaction mixture was quenched with acetic acid (10.6 mL, 188 mmol)in THF (50 mL), stirred at 15° C. for 16 h, poured into water (1000 mL)and extracted with EtOAc (3×500 mL). The combined organic layers werewashed with brine (1500 mL), dried over anhydrous Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by flashcolumn (0˜10% of EtOAc in PE) to give 8.3 (13 g, 80%) as an oil. ¹H NMR(400 MHz, CDCl₃) δ_(H) 4.29-4.19 (m, 2H), 2.23-2.08 (m, 1H), 1.96-1.59(m, 8H), 1.53-1.28 (m, 17H), 1.17-1.02 (m, 5H), 0.96-0.90 (m, 5H), 0.86(br d, J=6.8 Hz, 2H).

Synthesis of 8.4

To a solution of 8.3 (13 g, 30.0 mmol) and DME (150 mL) was addedRh₂(OAc)₄ (132 mg, 0.3 mmol) in one portion at 15° C. After stirring at15° C. for 2 h, the reaction mixture was concentrated to give 8.4 (13 g)as an oil, which was used as is.

Synthesis of 8.5

To a solution of 8.4 (13 g, 32.1) in MeOH (200 mL) was added KOH (18.0g, 321 mmol) at 15° C. After stirring 70° C. for 1 h, the reactionmixture was poured into H₂O (200 mL), and extracted with EtOAc (3×200mL). The combined organic layer was washed with HCl (1M, 100 mL),saturated NaHCO₃ (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0˜15% of EtOAc in PE) to give 8.5 (8.3 g, 78.3%) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H) 2.61 (dt, J=6.8, 13.9 Hz, 1H), 2.27-2.15 (m, 1H),2.08-2.02 (m, 1H), 1.87-1.49 (m, 13H), 1.48-1.20 (m, 12H), 1.18-1.10 (m,1H), 1.08 (s, 3H), 1.03-0.96 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Synthesis of 8.6

To a suspension of Ph₃PEtBr (27.6 g, 74.6 mmol) in anhydrous THF (100mL) was added t-BuOK (11.1 g, 99.6 mmol) at 15° C. under N₂. Afterstirring at 40° C. for 30 min, a solution of 8.5 (8.3 g, 24.9 mmol) inanhydrous THF (50 mL) was dropwise. After stirring at 40° C. for 16 h,the mixture was cooled, poured into ice-water (150 mL), stirred for 10min, and extracted with EtOAc (2×100 mL). The combine organic phase waswashed with brine (2×200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by trituration with MeOH/H₂O(1:1, 320 mL) at reflux to give 8.6 (5.3 g, 62%) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H) 5.24-5.00 (m, 1H), 2.50 (br d, J=13.8 Hz, 1H),2.25-2.10 (m, 1H), 2.01-1.56 (m, 10H), 1.48-1.16 (m, 14H), 1.05 (s, 3H),0.92-0.80 (m, 10H).

Synthesis of 8.7

To a solution of 8.6 (5.3 g, 15.3 mmol) in THF (100 ml) was added BH₃Me₂S (4.58 mL, 45.9 mmol) at 0° C. After stirring at 15° C. for 16 h,the reaction mixture was cooled (0° C.) and treated with sequentiallyEtOH (8.91 ml, 203 mmol, 0.789 g/ml), NaOH (30.5 mL, 5M, 153 mmol) andH₂O₂ (15.3 mL, 153 mmol, 1.13 g/mL, 30% in water) dropwise added slowlyuntil the inner temperature no longer rises and the inner temperaturewas maintained below 30° C. After stirring at 50° C. for 1 h, thereaction was quenched with saturated aqueous Na₂S₂O₃ (130 mL) andstirred at 0° C. for another 1 hour. The reaction was checked bypotassium iodide-starch test paper to confirm excess H₂O₂ was destroyed(did not changed to blue). The aqueous phase was extracted with DCM(3×50 mL). The combine organic phase was washed with saturated Na₂S₂O₃(2×100 mL), brine (2×100 mL), dried over anhydrous Na₂SO₄ filtered andconcentrated to give 8.7 (4.3 g) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=2.47 (br d, J=5.2 Hz, 0.4H), 2.29 (dd, J=3.2, 12.8 Hz, 0.6H), 2.13(d, J=3.2 Hz, 3H), 1.88-1.66 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.14 (m,13H), 1.11-0.80 (m, 13H).

Synthesis of 8.8

To a mixture of PCC (3.70 g, 17.2 mmol) and silica gel (4 g) in DCM (20mL) was added 8.7 (2.5 g, 6.89 mmol) in DCM (30 mL) at 25° C. Afterstirring at 25° C. for 1 h, the reaction mixture was filtered and washedwith DCM (100 mL). The filtrate was collected and concentrated to give8.8 (1.93 g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=2.47 (br d, J=5.2Hz, 0.4H), 2.29 (dd, J=3.2, 12.8 Hz, 0.6H), 2.13 (d, J=3.2 Hz, 3H),1.88-1.66 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.14 (m, 13H), 1.11-0.80 (m,13H).

Synthesis of 8.9

To a solution of 8.8 (1.93 g, 5.35 mmol) in MeOH (20 mL) at 0° C. wasadded MeONa (4.33 g, 80.2 mmol). After stirring at 70° C. for 16 h, thereaction mixture was added to saturated NH₄Cl (10 mL) and extracted withEtOAc (2×10 mL). The combined organic phase was washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 8.9(1.2 g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=2.30 (dd, J=3.2, 12.7Hz, 1H), 2.14 (s, 3H), 1.82 (br d, J=12.4 Hz, 2H), 1.76-1.63 (m, 5H),1.57-1.43 (m, 7H), 1.40-1.23 (m, 10H), 1.07-0.84 (m, 12H).

Synthesis of 8.10

To a mixture of MePPh₃Br (9.46 g, 26.5 mmol) in THF (20 mL) was addedt-BuOK (2.96 g, 26.5 mmol) at 25° C. under N₂. After stirring at 50° C.for 30 mins, 8.9 (1.2 g, 3.32 mmol) in THF (10 mL) was added at 25° C.After stirring at 60° C. for 3 h, the reaction mixture was cooled,poured to ice water (50 mL), and extracted with EtOAc (2×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand concentrated. The residue was purified by flash column (0˜30% ofEtOAc in PE) to give 8.10 (1.1 g) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=4.80 (s, 1H), 4.61 (s, 1H), 1.83 (br d, J=14.4 Hz, 2H), 1.70-1.57(m, 6H), 1.53-1.43 (m, 4H), 1.40-1.22 (m, 12H), 1.19-1.04 (m, 2H),0.99-0.87 (m, 9H), 0.82 (s, 3H).

Synthesis of 8.11

To a solution of 8.10 (500 mg, 1.39 mmol) in DCM (10 mL) was addedm-CPBA (446 mg, 2.08 mmol, 80%) at 25° C. After stirring at 25° C. for 2h, the mixture was quenched with sat. NaHCO₃ and Na₂S₂O₃ (40 mL,v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phasewas washed with sat. NaHCO₃ and Na₂S₂O₃ (50 mL, v:v=1:1), dried overNa₂SO₄, filtered and concentrated to give 8.11 (520 mg) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.70 (br d, J=5.2 Hz, 1H), 2.65-2.49 (m, 1H),1.91-1.78 (m, 7H), 1.70-1.61 (m, 10H), 1.31 (br d, J=7.6 Hz, 10H),0.96-0.88 (m, 14H).

Synthesis of 8 & 9

To a solution of 8.11 (300 mg, 0.8008 mmol) in DMF (5 mL) were addedCs₂CO₃ (782 mg, 2.40 mmol) and 1H-pyrazole-4-carbonitrile (186 mg, 2.00mmol). After stirring at 130° C. for 12 h, the mixture was added intosaturated NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with LiCl (100 mL, 5% in water), brine (2×100mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash column (0˜50% of EtOAc in PE) to afford a mixtureof diastereomers 8 & 9 (165 mg) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=7.92 (s, 1H), 7.79 (s, 1H), 4.38-4.33 (m, 1H), 4.26-4.18 (m, 1H),2.32 (br d, J=13.2 Hz, 5H), 1.77-1.61 (m, 11H), 1.37-1.28 (m, 10H),1.00-0.91 (m, 15H).

The C20 diastereomers were separated by SFC (Column DAICEL CHIRALCEL OD(250 mm*30 mm, 10 um); Condition 0.1% NH₃H₂O EtOH; FlowRate (ml/min) 70)to give 8 (67.3 mg, 32.2%) and 9 (11 mg) as solids. 9 (11 mg) wasfurther purified by SFC (Column DAICEL CHIRALCE OD (250 mm×30 mm, 10um); Condition 0.1% NH₃H₂O EtOH; FlowRate (ml/min) 70) to give 9 (6.5mg) as a solid.

8: ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.92 (s, 1H), 7.79 (s, 1H), 4.39-4.32(m, 1H), 4.26-4.20 (m, 1H), 2.43 (s, 1H), 2.32 (br d, J=12.8 Hz, 1H),1.91-1.64 (m, 6H), 1.55-1.18 (m, 18H), 1.03-0.82 (m, 15H). LC-ELSD/MSpurity 99%, MS ESI calcd for C₂₉H₄₂N₃ [M−2H₂O+H]⁺ 432.3, found 432.3.SFC 98.54% de

9: ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.88 (s, 1H), 7.85 (s, 1H), 4.31-4.24(m, 1H), 4.02-3.96 (m, 1H), 3.06 (s, 1H), 2.43-2.34 (m, 1H), 1.85-1.73(m, 2H), 1.70-1.59 (m, 4H), 1.54-1.42 (m, 12H), 1.36-1.30 (m, 3H),1.30-1.23 (m, 5H), 1.18 (s, 1H), 1.16-1.04 (m, 2H), 1.00 (s, 1H),0.95-0.87 (m, 6H), 0.86-0.71 (m, 3H). LC-ELSD/MS purity 99%, MS ESIcalcd for C₂₉H₄₂N₃ [M−2H₂O+H]⁺ 432.3, found 432.3. SFC 99.02% de.

Example 10 & 11: Synthesis of1-((S)-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile&1-((R)-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile

Synthesis of 10.2

To a solution of 1.1 (50 g, 182 mmol) in MeOH (600 mL) was added4-methylbenzenesulfonic acid (6.26 g, 36.4 mmol) at 25° C. Afterstirring at 55° C. for 16 h, the mixture was diluted with Et₃N (20 mL).The solid was filtered and the filtrate concentrated to afford 10.2 (52g, 89.1%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.73-0.83 (m, 1H),0.91 (s, 3H), 0.98-1.13 (m, 2H), 1.20-1.56 (m, 16H), 1.72-1.78 (m, 1H),1.80-1.86 (m, 2H), 1.88-1.99 (m, 2H), 2.05-2.16 (m, 2H), 2.25-2.35 (m,3H), 2.38-2.51 (m, 2H), 3.15 (s, 1H), 3.21 (s, 1H), 3.50 (s, 6H).

Synthesis of 10.3

To a solution of 10.2 (4.5 g, 14.0 mmol) and ethyl diazoacetate (7.35 mLg, 1.085 g/mL, 70.0 mmol) in THF (300 mL) was added the fresh preparedLDA (67.1 mL, 1.0 M, 67.1 mmol) at −78° C. After stirring at −78° C. for2 h, the reaction was quenched with acetic acid (4.00 mL, 1.0492 g/mL,70.0 mmol) in THF (100 mL). After stirring at 15° C. for 16 h, hemixture was added to NH₄Cl (200 mL) and extracted with EtOAc (2×125 mL).The combined organic layers were washed with brine (150 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-10% of EtOAc in PE) to give 10.3 (3.7 g, 60.8%) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.77-4.64 (m, 1H), 4.25 (dq, J=1.6,7.2 Hz, 2H), 3.20 (s, 3H), 3.14 (s, 3H), 2.22-2.01 (m, 2H), 1.96-1.76(m, 4H), 1.69-1.61 (m, 2H), 1.55-1.42 (m, 1H), 1.41-1.27 (m, 5H),1.27-0.96 (m, 9H), 0.93 (s, 3H), 0.91-0.83 (m, 1H), 0.80-0.62 (m, 2H).

Synthesis of 10.4

To a solution of 10.3 (57 g, 147 mmol) and DME (500 mL) was addedRh₂(OAc)₄ (800 mg, 1.81 mmol) in one portion at 15° C. After stirring at15° C. for 2 h, the reaction mixture was concentrated to give 10.4 (59.7g) as an oil, which was used as is.

Synthesis of 10.5

To a solution of 10.4 (59.7 g) in MeOH (500 mL) was added KOH (81.9 g,1460 mmol) at 15° C. After stirring at 70° C. for 1 h, the reactionmixture was poured into H₂O (500 mL) and extracted with EtOAc (3×200mL). The combined organic layer was washed with HCl (1M, 100 mL),saturated NaHCO₃ (100 mL), and brine (200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashcolumn (0˜15% of EtOAc in PE) to give 10.5 (30 g, 61.4%) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 3.21 (d, J=1.2 Hz, 3H), 3.15 (d, J=1.6 Hz,3H), 2.24-2.01 (m, 3H), 1.98-1.78 (m, 5H), 1.76-1.61 (m, 2H), 1.59-1.13(m, 8H), 1.10 (d, J=6.4 Hz, 3H), 1.08-0.82 (m, 5H), 0.78-0.62 (m, 2H).

Synthesis of 10.6

To a mixture of EtPPh₃Br (99.4 g, 268 mmol) in THF (400 mL) was addedt-BuOK (30.0 g, 268 mmol) at 15° C. under N₂. After stirring at 15° C.for 30 min, 10.5 (30 g, 89.6 mmol) in THF (100 mL) was added. Afterstirring at 40° C. for 1 h, the mixture was poured into sat. NH₄Claqueous solution (400 mL) and extracted with EtOAc (2×200 mL). Thecombined organic layer was washed with brine (200 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 10.6 as a residue,which was used directly for the next step.

Synthesis of 10.7

To a solution of 10.6 (31 g, 89.4 mmol) in THF (300 mL) was added HCl(89.4 mL, 1 M, 89.4 mmol). After stirring at 15° C. for 2 h, the mixturewas poured into NaHCO₃ aq (200 mL) and extracted with EtOAc (2×150 mL).The combined organic phase was washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0˜3% of EtOAc in PE) to give 10.7 (14 g, 52.2%) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.25-5.07 (m, 1H), 2.45-2.36 (m,1H), 2.35-2.12 (m, 4H), 2.07 (t, J=13.2 Hz, 1H), 1.95-1.81 (m, 3H),1.80-1.64 (m, 5H), 1.27-1.08 (m, 9H), 0.99-0.93 (m, 2H), 0.93-0.74 (m,6H).

Synthesis of 10.8

A stirred solution of trimethylsulfoxonium iodide (10.2 g, 46.5 mmol)and t-BuOK (6.81 g, 55.8 mmol) in DMSO (60 mL) and THF (20 mL) washeated at 40° C. for 1 h under N₂. The reaction mixture was added to10.7 (14 g, 46.5 mmol) in DMSO (20 mL). After stirring at 40° C. for 30min, the reaction was diluted with water (250 mL) to give a solid. Theprecipitate was filtered, dried under reduced pressure to afford 10.8(12.5 g, 85.6%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.32-5.01 (m,1H), 2.64 (s, 2H), 2.55-2.48 (m, 1H), 2.28-2.10 (m, 1H), 2.03-1.96 (m,1H), 1.90-1.80 (m, 3H), 1.80-1.58 (m, 7H), 1.47-1.21 (m, 4H), 1.12 (brs, 4H), 1.10-1.01 (m, 3H), 0.95 (s, 2H), 0.92-0.64 (m, 5H).

Synthesis of 10.9

To a suspension of CuCN (4.21 g, 47.4 mmol) in THF (120 mL) at −40° C.was added MeLi (59.2 mL, 94.8 mmol, 1.6 M). After stirring at −40° C.for 1 h, 10.8 (5 g, 15.8 mmol) in THF (30 mL) was added at −40° C. Afterstirring at 25° C. for 2 h, the reaction was slowly poured into 10%NH₄Cl (20 mL) and extracted with EtOAc (2×50 mL). The combined organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄filtered and concentrated to give 10.9 (4.5 g, 86.2%) as a solid. ¹H NMR(400 MHz, CDCl3) δH 5.23-5.05 (m, 1H), 2.30-2.09 (m, 1H), 2.04-1.70 (m,7H), 1.56-1.39 (m, 4H), 1.39-1.23 (m, 4H), 1.22-0.95 (m, 10H), 0.95-0.83(m, 8H), 0.83-0.55 (m, 3H).

Synthesis of 10.10

To a solution of 10.9 (5.5 g, 16.6 mmol) in THF (100 mL) was addedBH₃Me₂S (4.97 mL, 49.8 mmol, 10 M) at 0° C. After stirring at 20° C. for12 h, the resulting mixture was treated with ethanol (20 mL) and NaOHaqueous (33.2 mL, 5.0 M) at 0° C. Hydrogen peroxide (19.9 mL, 10 M) wasthen added dropwise at 0° C. After stirring for 2 h, the reaction wasquenched with saturated aqueous Na₂S₂O₃ (30 mL) and extracted with EtOAc(2×30 mL). The combined organic phase was washed with brine (2×20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give 10.10(5.5 g, 95.1%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H) 1.95-1.73 (m,5H), 1.72-1.55 (m, 7H), 1.54-1.39 (m, 5H), 1.21-1.04 (m, 7H), 1.04-0.96(m, 5H), 0.94-0.84 (m, 6H), 0.83-0.55 (m, 5H).

Synthesis of 10.11

To a solution of 10.10 (5.5 g, 15.7 mmol) in DCM (100 mL) was added PCC(10.1 g, 47.0 mmol) and silica gel (12 g) at 25° C. After stirring at25° C. for 1 h, the reaction mixture was filtered and the filter cakewas washed with DCM (2×20 mL). The combined organic layer wasconcentrated under reduced pressure. The residue was purified by column(15-20% of EtOAc in PE) to give 10.11 (4.4 g, 81.4%) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H) 2.50-2.25 (m, 1H), 2.17-2.09 (m, 3H), 1.87-1.67(m, 6H), 1.50-1.38 (m, 4H), 1.36-1.17 (m, 5H), 1.17-0.94 (m, 7H),0.93-0.92 (m, 3H), 0.91-0.87 (m, 4H), 0.87-0.54 (m, 5H).

Synthesis of 10.12

To a solution of 10.11 (1.4 g, 4.03 mmol) in MeOH (50 mL) at 0° C. wasadded MeONa (3.26 g, 60.4 mmol). After stirring at 70° C. for 16 h, thereaction mixture was added to saturated NH₄Cl (100 mL) and extractedwith EtOAc (2×100 mL). The combined organic phase was washed withsaturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 10.12 (1.2 g, 86.3%) as an oil. ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.31 (dd, J=3.2, 12.8 Hz, 1H), 2.15 (s, 3H), 1.88-1.60 (m,8H), 1.56-1.29 (m, 7H), 1.24-0.95 (m, 8H), 0.95-0.88 (m, 7H), 0.87-0.55(m, 4H).

Synthesis of 10.13

To a mixture of MePPh₃Br (6.57 g, 18.4 mmol) in THF (40 mL) was addedt-BuOK (2.06 g, 18.4 mmol) at 15° C. under N₂. After stirring at 15° C.for 30 min, 10.12 (800 mg, 2.30 mmol) in THF (10 mL) was added. Afterstirring at 40° C. for 2 h, the reaction mixture was poured into NH₄Claq (150 mL) and extracted with EtOAc (2×200 mL). The combined organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(12˜20% of EtOAc in PE) to give 10.13 (650 mg, 82.0%) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H) 4.81 (s, 1H), 4.62 (d, J=1.6 Hz, 1H), 1.90-1.75(m, 4H), 1.73 (s, 3H), 1.73-1.58 (m, 5H), 1.56-1.20 (m, 8H), 1.12-0.94(m, 7H), 0.91 (t, J=7.6 Hz, 4H), 0.87-0.83 (m, 4H), 0.82-0.56 (m, 3H).

Synthesis of 10.14

To a solution of 10.13 (450 mg, 1.30 mmol) in DCM (15 mL) was addedm-CPBA (527 mg, 85%, 2.60 mmol). After stirring at 0° C. for 1 h, themixture was quenched with NaHCO₃ (50 mL, sat. aq.) and Na₂S₂O₃ (20 mL,sat. aq.). The organic layer was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give 10.14 (360 mg, 76.9%) asa solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.77-2.70 (m, 1H), 2.68-2.61 (m,1H), 1.87-1.72 (m, 6H), 1.52-1.41 (m, 5H), 1.30-1.23 (m, 9H), 0.94-0.90(m, 7H), 0.89-0.87 (m, 3H), 0.86-0.59 (m, 8H).

Synthesis of 10 & 11

To a solution of 10.14 (360 mg, 0.998 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (185 mg, 1.99 mmol) and Cs₂CO₃ (648 mg, 1.99mmol) at 20° C. After stirring at 130° C. for 2 h, the mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was separated, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (30˜65% EtOAc inPE) to give a mixture of diastereomers 10 & 11 (200 mg, 44.2% yield) asa solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.93 (s, 1H), 7.80 (s, 1H),4.41-4.35 (m, 1H), 4.27-4.21 (m, 1H), 2.50 (s, 1H), 2.41-2.26 (m, 1H),1.91-1.72 (m, 8H), 1.53-1.39 (m, 7H), 1.17-1.06 (m, 3H), 1.01 (s, 3H),0.97 (s, 3H), 0.94-0.89 (m, 5H), 0.87-0.83 (m, 5H), 0.78-0.55 (m, 3H).

The diastereomers were separated by SFC: Column: DAICEL CHIRALCEL OJ-H250 mm×30 mm, 5 um; Condition: 0.1% NH₃H₂O EtOH; Gradient: from 25% to25% of B; Flow rate: 60 mL/min; Column temperature: 40° C.) to afford 11(30 mg) and 10 (130.5 mg) as solids. 11 was re-purified by SFC: Column:DAICEL CHIRALCEL OJ-H 250 mm×30 mm, 5 um; Condition: 0.1% NH₃H₂O EtOH;Gradient: from 20% to 20% of B; Flow rate: 60 mL/min; Columntemperature: 40° C.) to afford 11 (16.9 mg) as a solid.

10: ¹H NMR (400 MHz, CDCl3) δ_(H) 7.93 (s, 1H), 7.80 (s, 1H), 4.40-4.35(m, 1H), 4.26-4.21 (m, 1H), 2.47 (s, 1H), 2.35-2.29 (m, 1H), 1.91-1.59(m, 9H), 1.53-1.35 (m, 6H), 1.33-1.23 (m, 3H), 1.18-1.03 (m, 3H), 1.01(s, 3H), 0.99-0.95 (m, 5H), 0.91 (t, J=7.6 Hz, 4H), 0.87-0.68 (m, 3H),0.66-0.55 (m, 1H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄₀N₃[M−2H₂O+H]⁺ 418.3 found 418.3. SFC: 95% de.

11: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.84 (s, 1H), 4.28 (d,J=13.6 Hz, 1H), 4.01 (d, J=13.6 Hz, 1H), 3.00 (s, 1H), 2.41-2.34 (m,1H), 1.84-1.57 (m, 9H), 1.52-1.40 (m, 6H), 1.19 (s, 3H), 1.10-1.06 (m,3H), 1.11-1.05 (m, 1H), 1.02 (s, 3H), 1.01-0.93 (m, 5H), 0.93-0.89 (m,4H), 0.78-0.66 (m, 3H), 0.62-0.54 (m, 1H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₈H₄₀N₃ [M−2H₂O+H]⁺ 418.3 found 418.3. SFC: 99% de.

Example 12 &13: Synthesis of1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile&1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile

Synthesis of 12.1

To the fresh prepared MAD (310 mmol) solution in toluene (300 mL) wasadded (5β)-androstane-3,17-dione, 12.0 (30 g, 104 mmol) in DCM (100 mL)dropwise at −70° C. After stirring at −70° C. for 1 h under N₂, n-PrMgCl(130 mL, 260 mmol, 2M) was added dropwise at −70° C. After stirring at−70° C. for 4 h, the reaction mixture was poured into saturated aqueouscitric acid (1000 mL) at 10° C. and extracted with EtOAc (2×1000 mL).The combined organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn (0˜30% of EtOAc in PE) to give 12.1 (16 g, 47.7%) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.49-2.38 (m, 1H), 2.17-2.00 (m, 1H),1.98-1.76 (m, 4H), 1.74-1.66 (m, 1H), 1.62-1.40 (m, 10H), 1.38-1.15 (m,9H), 1.12-0.99 (m, 1H), 0.98-0.90 (m, 6H), 0.84 (s, 3H).

Synthesis of 12.2

To a freshly prepared LDA (150 mmol) solution in THF (100 mL) was addeda solution of 12.1 (10 g, 30.0 mmol) and ethyl diazoacetate (19.0 g, 150mmol, 90%) in THF (200 mL) at −70° C. After stirring at −70° C. for 2 h,the reaction was quenched with acetic acid (8.57 mL, 150 mmol) in THF(20 mL). After warming to rt overnight, the reaction was diluted withwater (300 mL) and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with brine (300 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0˜20% of EtOAc in PE) to give 12.2 (13 g, 97.7%) as an oil. ¹H NMR (400MHz, CDCl₃) δ_(H) 4.75-4.65 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.20-2.09(m, 1H), 1.93-1.76 (m, 3H), 1.72-1.35 (m, 14H), 1.34-1.24 (m, 7H),1.23-0.99 (m, 5H), 0.96-0.91 (m, 6H), 0.89 (s, 3H).

Synthesis of 12.3

To a solution of 12.2 (13 g, 29.1 mmol) in DME (130 mL) was addedRh₂(OAc)₄ (300 mg, 0.6787 mmol) in one portion at 15° C. After stirringat 15° C. for 16 h, the reaction was diluted with water (300 mL) andextracted with EtOAc (3×200 mL). The combined organic layers were washedwith brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 12.3 (11 g, 90.9%) as an oil.

Synthesis of 12.4

To a solution of 12.3 (11 g, 26.2 mmol) in MeOH (110 mL) was added KOH(14.6 g, 262 mmol) at 20° C. After stirring for 3 hours at 70° C., thereaction mixture was added to saturated brine (100 mL) and extractedwith DCM (2×200 mL). The combined organic layer was washed with HCl (200mL, 1N), saturated NaHCO₃ (200 mL), saturated brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give 12.4 (11 g) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H) 2.61 (dt, J=6.8, 14.0 Hz, 1H), 2.24-2.15 (m, 1H),2.09-2.01 (m, 1H), 1.91-1.68 (m, 6H), 1.67-1.43 (m, 10H), 1.42-1.19 (m,10H), 1.06 (s, 3H), 0.96-0.90 (m, 6H).

Synthesis of 12.5

To a mixture of EtPPh₃Br (38.2 g, 103 mmol) in THF (160 mL) was addedt-BuOK (11.5 g, 103 mmol) at 20° C. under N₂. After stirring at 40° C.for 30 min, 12.4 (9.0 g, 25.9 mmol) was added at 40° C. After stirringat 40° C. for 16 h, the reaction mixture was quenched with saturatedNH₄Cl aqueous (150 mL) at 20° C. and extracted with EtOAc (2×100 mL).The combined organic phase was concentrated. The residue was purified byflash column (0˜20% of EtOAc in PE) to give 12.5 (4.2 g, 45.2%) as asolid. ¹H NMR (400 MHz, CDCl₃) δH 5.25-5.05 (m, 1H), 2.54-2.10 (m, 1H),1.99-1.69 (m, 7H), 1.67-1.57 (m, 4H), 1.54-1.20 (m, 16H), 1.05-0.98 (m,4H), 0.96-0.86 (m, 9H)

Synthesis of 12.6

To a solution of 12.5 (4.2 g, 11.7 mmol) in THF (40 mL) was addedBH₃.Me₂S (3.51 mL, 10 M, 35.1 mmol). After stirring at 15° C. for 16 h,the reaction was treated sequentially with EtOH (6.73 mL, 117 mmol),NaOH (4.67 g in 23.4 mL water, 5 M, 117 mmol) dropwise and H₂O₂ (11.7mL, 10 M, 117 mmol) dropwise at 0° C. After stirring 70° C. for 2 h, themixture was quenched by Na₂SO₃ (100 mL, 10%) and extracted with EtOAc(2×100 mL). The combined organic layer was separated, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give 12.6 (4.2 g) asa solid, which was used as is.

Synthesis of 12.7

To a solution of 12.6 (4.2 g, 11.1 mmol) in DCM (50 mL) was added DMP(9.41 g, 22.2 mmol). After stirring at 20° C. for 1 h, the mixture wasquenched by NaHCO₃ (100 mL, saturated) and Na₂S₂O₃ (100 mL, saturated).The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated to give 12.7 (4.0 g) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H) 2.50-2.24 (m, 1H), 2.16-2.10 (m, 3H), 1.93-1.64 (m, 7H), 1.54-1.43(m, 6H), 1.39-1.12 (m, 11H), 1.05-0.82 (m, 14H)

Synthesis of 12.8

To a solution of 12.7 (3.5 g, 9.34 mmol) in MeOH (80 mL) at 0° C. wasadded MeONa (10.0 g, 186 mmol). After stirring at 80° C. for 16 h, thereaction mixture was concentrated. The residue was diluted withsaturated NH₄Cl (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic phase was washed with saturated brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give 12.8 (2.2 g,63.0%) as a solid. ¹H NMR (400 MHz, CDCl₃) 2.32-2.25 (m, 1H), 2.13 (s,3H), 1.89-1.75 (m, 3H), 1.74-1.56 (m, 5H), 1.52-1.40 (m, 6H), 1.39-1.17(m, 10H), 1.04-0.96 (m, 2H), 0.95-0.92 (m, 4H), 0.91-0.89 (m, 6H),0.89-0.82 (m, 1H); LC-ELSD/MS: purity>99%, MS ESI calcd. for C₂₅H₄₁O[M−H2O+H]⁺ 357.3, found 357.3.

Synthesis of 12.9

To a mixture of MePPh₃Br (3.78 g, 10.6 mmol) in THF (16 mL) was addedt-BuOK (1.18 g, 10.6 mmol) at 20° C. under N₂. After stirring at 50° C.for 30 min, 12.8 (1.0 g, 2.66 mmol) was added at 50° C. After stirringat 50° C. for 16 h, the reaction mixture was quenched with saturatedNH₄Cl aqueous (150 mL) at 20° C. and extracted with EtOAc (2×100 mL).The combined organic phase was concentrated. The residue was purified byflash column (0˜20% of EtOAc in PE) to give 12.9 (700 mg, 70.6%) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.80 (s, 1H), 4.60 (d, J=2.0 Hz,1H), 1.87-1.58 (m, 12H), 1.54-1.23 (m, 17H), 1.12-0.97 (m, 3H),0.96-0.91 (m, 4H), 0.90 (s, 3H), 0.80 (s, 3H).

Synthesis of 12.10

To a solution of 12.9 (700 mg, 1.87 mmol) in DCM (10 mL) was addedm-CPBA (758 mg, 3.74 mmol). After stirring at 20° C. for 1 h, themixture was quenched by NaHCO₃ (20 mL, saturated) and Na₂S₂O₃ (20 mL,saturated). The organic layer was separated, dried over Na₂SO₄, filteredand concentrated to give 12.10 (700 mg) as a solid, which was used asis.

Synthesis of 12 & 13

To a solution of 12.10 (400 mg, 1.02 mmol) in DMF (20 mL) was added1H-pyrazole-4-carbonitrile (189 mg, 2.04 mmol) and Cs₂CO₃ (668 mg, 2.04mmol) at 20° C. After stirring at 120° C. for 48 h, the reaction mixturewas diluted with water (50 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash column (5˜40% EtOAc in PE) to give a mixture ofdiastereomers of 12 & 13 (350 mg, 71.2%) as a solid. 12 & 13 (350 mg,0.7 mmol) was separated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30mm, 5 um); Mobile phase: A: CO₂ B: 0.1% NH₃H₂O EtOH; gradient: from 20%to 20% of B, FlowRate (ml/min): 60) to give 12 (41.0 mg, 11.7%) and 13(98.4 mg, 28.1%) both as a solid.

12: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.87 (s, 1H), 4.33-3.94(m, 2H), 3.06 (s, 1H), 2.45-2.35 (m, 1H), 1.87-1.61 (m, 5H), 1.52-1.20(m, 15H), 1.18 (s, 3H), 1.13-1.01 (m, 3H), 0.98 (s, 3H), 0.93 (t, J=7.2Hz, 4H), 0.87 (s, 3H), 0.85-0.66 (m, 3H). LC-ELSD/MS: purity>99%,analytic SFC: 97.84% de; MS ESI calcd. for C₃₀H₄₄N₃ [M−2H₂O+H]⁺ 446.4,found 446.4.

13: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.91 (s, 1H), 7.79 (s, 1H), 4.39-4.19(m, 2H), 2.40 (s, 1H), 2.36-2.29 (m, 1H), 1.91-1.63 (m, 7H), 1.53-1.41(m, 7H), 1.40-1.10 (m, 13H), 0.98 (s, 3H), 0.96-0.91 (m, 7H), 0.90-0.85(m, 4H); LC-ELSD/MS: purity>99%, analytic SFC: 99.64% de; MS ESI calcd.for C₃₀H₄₄N₃ [M−2H₂O+H]⁺ 446.4, found 446.4.

Example 14 & 15: Synthesis of1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile&1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile

Synthesis of 14.1

To the fresh prepared MAD (519 mmol) solution in toluene (1 L) was addeda solution of 12.0 (50.0 g, 173 mmol) in DCM (200 mL) dropwise at −70°C. After stirring at −70° C. for 1 h under N₂, MeMgBr (173 mL, 519 mmol,3 M in ethyl ether) was added dropwise at −70° C. After stirring at −70°C. for 2 h, the reaction mixture was poured into saturated aqueouscitric acid (1000 mL) at 10° C. and extracted with EtOAc (2×400 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel chromatography (PE/EtOAc=10/1 to3/1) to afford 14.1 (36 g, 68%) as a solid. ¹HNMR (400 MHz, CDCl₃)δ_(H)2.48-2.38 (m, 1H), 2.13-2.02 (m, 1H), 1.98-1.85 (m, 3H), 1.83-1.69(m, 2H), 1.63-1.43 (m, 8H), 1.39-1.14 (m, 10H), 1.12-1.02 (m, 1H), 0.97(s, 3H), 0.84 (s, 3H).

Synthesis of 14.2

To the fresh prepared LDA (82.1 mmol) solution in THF (100 mL) was asolution of 14.1 (6 g, 19.7 mmol) and ethyl diazoacetate (12.4 g, 98.4mmol, 90%) in THF (120 mL) at −70° C. After stirring at −70° C. for 2 h,the reaction was quenched with acetic acid (5.61 mL, 98.4 mmol) in THF(15 mL), warmed to 20° C. for 16 h, diluted with water (300 mL) andextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜15% of EtOAcin PE) to give 14.2 (8.0 g, 97%) as an oil. HNMR (400 MHz, CDCl₃) δ_(H)4.69 (br s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.18-2.08 (m, 1H), 2.04 (s,1H), 2.01-1.93 (m, 1H), 1.91-1.78 (m, 2H), 1.76-1.63 (m, 2H), 1.60-1.38(m, 9H), 1.35-1.29 (m, 4H), 1.28-1.23 (m, 5H), 1.14-0.98 (m, 4H), 0.94(s, 3H), 0.89 (s, 3H).

Synthesis of 14.3

To a solution of 14.2 (8.0 g) in DME (100 mL) was added Rh₂(OAc)₄ (211mg, 0.48 mmol) in one portion at 15° C. After stirring at 30° C. for 12h, the mixture was diluted with H₂O (100 mL) and extracted with EtOAc(3×60 mL). The combined organic phase was washed with brine (2×30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to afford 14.3(7.7 g) as an oil. ¹HNMR (400 MHz, CDCl₃) δ_(H) 12.41 (s, 1H), 4.24-4.15(m, 2H), 3.74-2.27 (m, 2H), 2.22-2.11 (m, 1H), 1.98-1.69 (m, 5H),1.57-1.35 (m, 8H), 1.32-1.24 (m, 9H), 1.22-1.01 (m, 7H), 0.96-0.90 (m,3H).

Synthesis of 14.4

To a solution of 14.3 (7.7 g, 19.7 mmol) in MeOH (100 mL) was added KOH(6.62 g, 118 mmol) at 15° C. After stirring at 70° C. for 1 h, thereaction mixture was poured into saturated brine (100 mL) and extractedwith EtOAc (3×100 mL). The combined organic layer was washed with HCl(1M, 100 mL), saturated NaHCO₃ (100 mL), brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 14.4 (5.8 g, 93%) asa solid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.66-2.55 (m, 1H), 2.23-2.16 (m,1H), 2.09-2.01 (m, 1H), 1.93-1.84 (m, 2H), 1.83-1.72 (m, 3H), 1.67-1.50(m, 6H), 1.44-1.31 (m, 5H), 1.30-1.13 (m, 7H), 1.09-0.99 (m, 5H), 0.93(s, 3H).

Synthesis of 14.5

To a mixture of Ph₃PEtBr (40.4 g, 109 mmol) in THF (160 mL) was addedt-BuOK (12.2 g, 21.8 mmol) at 20° C. under N₂. After stirring at 40° C.for 1 h, 14.4 (5.8 g, 18.2 mmol) was added. After stirring at 40° C. for2 h, the reaction mixture was quenched with 10% NH₄Cl aqueous (60 mL) at20° C. and extracted with EtOAc (2×100 mL). The combined organic phasewas washed with brine (50 mL) dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜15% of EtOAcin PE) to give 14.5 (5.3 g, 88%) as an oil. ¹HNMR (400 MHz, CDCl₃) δ_(H)5.20-5.09 (m, 1H), 2.55-2.10 (m, 2H), 2.01-1.70 (m, 7H), 1.66-1.58 (m,3H), 1.53-1.31 (m, 7H), 1.31-1.22 (m, 6H), 1.22-1.01 (m, 5H), 1.00-0.82(m, 7H).

Synthesis of 14.6

To a solution of 14.5 (5.3 g, 16 mmol) in THF (80 mL) was added BH₃.Me₂S(4.8 mL, 48 mmol, 10 M) under N₂. After stirring at 20° C. under N₂ for12 h, the mixture was cool to 0° C. and EtOH (16.5 mL, 288 mmol) andNaOH (57.6 mL, 5M, 288 mol) were added. H₂O₂ (28.8 mL, 10 M, 288 mmol)was then added dropwise. After stirring at 70° C. for 2 h, the mixturewas cooled, poured into Na₂S₂O₃ (500 mL, sat.), stirred for 30 min, andextracted with EtOAc (2×200 mL). The combined organic layer was washedwith saturated brine (2×100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give 14.6 (5.57 g) as a solid. ¹HNMR (400 MHz,CDCl₃) δ_(H) 1.97-1.72 (m, 5H), 1.70-1.67 (m, 1H), 1.55-1.34 (m, 8H),1.31-1.18 (m, 12H), 1.17-0.99 (m, 5H), 0.97-0.85 (m, 8H), 0.79-0.72 (m,1H).

Synthesis of 14.7

To a solution of 14.6 (5.57 g, 15.9 mmol) in DCM (120 mL) was added DMP(13.4 g, 31.8 mmol) at 20° C. After stirring at 20° C. for 1 h, themixture was quenched by saturated NaHCO₃ aqueous (100 mL). The DCM phasewas separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1,2×100 mL), brine (30 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash column (0-20% of EtOAc in PE) to give14.7 (4.95 g, 90%) as an oil. ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.48-2.25 (m,1H), 2.13 (d, J=1.6 Hz, 3H), 1.98-1.87 (m, 1H), 1.86-1.65 (m, 5H),1.63-1.43 (m, 8H), 1.42-1.28 (m, 5H), 1.24-1.14 (m, 5H), 1.08-0.92 (m,3H), 0.91-0.83 (m, 7H).

Synthesis of 14.8

To a solution of 14.7 (4.95 g, 14.2 mmol) in MeOH (80 mL) was addedMeONa (15.2 g, 283 mmol) in one portion under N₂. After stirring at 80°C. for 48 h, the mixture was diluted with H₂O (60 mL) and extracted withEtOAc (3×70 mL). The combined organic phase was washed with brine (50mL), dried over anhydrous Na₂SO₄, filtered and concentrated to afford14.8 (3.9 g) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.32-2.24 (m, 1H),2.13 (s, 3H), 1.97-1.89 (m, 1H), 1.87-1.66 (m, 5H), 1.57-1.32 (m, 9H),1.31-1.17 (m, 9H), 1.07-0.93 (m, 3H), 0.91-0.86 (m, 7H).

Synthesis of 14.9

To a mixture of MePPh₃Br (12.3 g, 34.6 mmol) in THF (50 mL) was addedt-BuOK (3.87 g, 34.9 mmol) at 20° C. under N₂. After stirring at 50° C.for 1 h, 14.8 (2.0 g, 5.8 mmol) was added at 50° C. After stirring at50° C. for 12 h, the reaction mixture was quenched with 10% NH₄Claqueous (100 mL) at 20° C. and extracted with EtOAc (2×80 mL). Thecombined organic phase was washed with brine (40 mL) dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0˜10% of EtOAc in PE) to give 14.9 (1.6 g, 81%) as an oil.¹HNMR (400 MHz, CDCl₃) δ_(H) 4.80 (s, 1H), 4.60 (s, 1H), 1.98-1.89 (m,1H), 1.86-1.74 (m, 3H), 1.69-1.55 (m, 5H), 1.54-1.47 (m, 3H), 1.47-1.36(m, 5H), 1.30-1.24 (m, 6H), 1.17-0.92 (m, 6H), 0.90 (s, 3H), 0.89-0.84(m, 3H), 0.80 (s, 3H).

Synthesis of 14.10

To a solution of 14.9 (1.5 g, 4.4 mmol) in DCM (30 mL) was added m-CPBA(1.76 g, 8.7 mmol, 85% purity) at 25° C. under N₂. After stirring at 25°C. for 4 h, the mixture was quenched by saturated NaHCO₃ aqueous (20 mL)and extracted with DCM (3×30 mL). The combined organic solution washedwith saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 30 mL), brine (20 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0˜20% of EtOAc in PE) to give 14.10 (1.52 g, 97%) as asolid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.73-2.62 (m, 2H), 1.87-1.72 (m,5H), 1.68-1.58 (m, 5H), 1.50-1.30 (m, 8H), 1.25 (s, 3H), 1.22 (s, 3H),1.07-0.96 (m, 2H), 0.93-0.88 (m, 8H), 0.87-0.71 (m, 4H).

Synthesis of 14 & 15

To a solution of 14.10 (1.52 g, 4.2 mmol) in DMF (30 mL) was added1H-pyrazole-4-carbonitrile (587 mg, 6.3 mmol) and Cs₂CO₃ (4.10 g, 12.6mmol) under N₂. After stirring at 130° C. for 72 h, the mixture wasdiluted with H₂O (40 mL) and extracted with EtOAc (3×50 mL). Thecombined organic phase was washed with H₂O (4×50 mL) and brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash column (0-35% of EtOAc in PE) to give to give amixture of diastereomers 14 & 15 (0.85 g) as a solid. ¹HNMR (400 MHz,CDCl₃) δ_(H) 7.94-7.88 (m, 1H), 7.81-7.77 (m, 1H), 4.38-4.27 (m, 1H),4.26-4.19 (m, 1H), 2.36-2.28 (m, 1H), 1.97-1.82 (m, 3H), 1.78-1.74 (m,2H), 1.74-1.65 (m, 4H), 1.64-1.56 (m, 2H), 1.55-1.32 (m, 10H), 1.31-1.28(m, 1H), 1.20-1.01 (m, 4H), 0.99-0.93 (m, 7H), 0.91-0.85 (m, 5H).

The diastereomers 14 & 15 (0.81 g) was separated by SFC (column: DAICELCHIRALCEL OD-H (250 mm*30 mm, 5 um), A; CO₂; B: 0.1% NH₃H₂O EtOH;gradient: 30-30%, flow rate: 50 mL/min) to afford 14 (112 mg) and 15(351.4 mg) both as solids.

14: ¹HNMR (400 MHz, CDCl₃) δ_(H) 7.89-7.87 (m, 1H), 7.87-7.86 (m, 1H),4.33-4.23 (m, 1H), 4.03-3.90 (m, 1H), 3.07 (s, 1H), 2.44-2.36 (m, 1H),1.95-1.86 (m, 1H), 1.84-1.65 (m, 4H), 1.51-1.44 (m, 3H), 1.43-1.34 (m,5H), 1.29-1.20 (m, 6H), 1.20-1.16 (m, 4H), 1.07-0.99 (m, 2H), 0.99-0.89(m, 5H), 0.89-0.83 (m, 4H), 0.83-0.66 (m, 3H); LC-ELSD/MS: purity 99%,analytic SFC: 99.74% de; MS ESI calcd. for C₂₈H₄₀N₃ [M−2H₂O+H]⁺ 418.3,found 418.3.

15: ¹HNMR (400 MHz, CDCl₃) δ_(H) 7.91 (s, 1H), 7.79 (s, 1H), 4.38-4.30(m, 1H), 4.26-4.19 (m, 1H), 2.41 (s, 1H), 2.37-2.30 (m, 1H), 1.97-1.71(m, 6H), 1.66-1.59 (m, 1H), 1.55-1.35 (m, 9H), 1.30-1.13 (m, 8H),1.08-0.94 (m, 8H), 0.93-0.85 (m, 5H); LC-ELSD/MS: purity 99%, analyticSFC: 100% de; MS ESI calcd. for C₂₈H₄₀N₃ [M−2H₂O+H]₊ 418.3, found 418.3.

Example 16 & 17: Synthesis of1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile&1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile

Synthesis of 16.2

To a mixture of (3α,5α) 3-hydroxy-androstan-17-one, 16.1 (10 g, 34.4mmol) in THE (100 mL) was added LDA (1 M, 160 mL, 160 mmol) at −70° C.under N₂. After stirring at −70° C. for 2 h, the reaction mixture wasquenched with HOAc (10.2 g, 171 mmol) in THF (100 mL) at 0° C. Afterwarming slowly to rt overnight, the reaction was diluted with water (400mL) and extracted with EtOAc (3×200 mL). The combined organic layerswere washed with brine (300 mL), dried over anhydrous Na₂SO₄, andevaporated under reduced pressure to give 16.2 (15 g) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H) 0.82 (s, 3H), 0.91 (s, 3H), 0.95-1.01 (m, 1H),1.05-1.15 (m, 2H), 1.26-1.33 (m, 6H), 1.35-1.52 (m, 6H), 1.54-1.73 (m,6H), 1.74-1.92 (m, 4H), 2.11-2.22 (m, 1H), 3.55-2.60 (m, 1H), 4.20-4.28(m, 2H), 4.69 (s, 1H).

Synthesis of 16.3

To a solution of 16.2 (10 g, 24.7 mmol) and DME (200 mL) was addedRh₂(OAc)₄ (196 mg, 0.4445 mmol) in one portion at 15° C. After stirringat 15° C. for 16 h under N₂, the reaction mixture was concentrated togive 16.3 (10.5 g) as solid, which was used directly for the next stepwithout purification. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.65-0.88 (m, 4H),0.93-1.12 (m, 7H), 1.21-1.38 (m, 7H), 1.37-1.28 (m, 6H), 1.64-1.88 (m,5H), 1.91-2.36 (m, 4H), 3.51-3.63 (m, 1H), 4.12-4.26 (m, 2H).

Synthesis of 16.4

To a solution of NaOH (2.64 g, 66.0 mmol) in H₂O (20 mL) was added 16.3(5 g, 13.2 mmol) in MeOH (100 mL)/THF (30 mL). After stirring at 60° C.for 16 h, the reaction mixture was poured into H₂O (100 mL) andextracted with EtOAc (3×200 mL). The combined organic layer was washedwith HCl (1M, 100 mL), saturated NaHCO₃ (100 mL), brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by trituration with EtOAc/PE (3:1, 100 mL) at 15° C. to give16.4 (2.5 g, 50%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.62-0.65(m, 1H), 0.79 (s, 3H), 1.08 (s, 3H), 1.24-1.38 (m, 6H), 1.41-1.63 (m,9H), 1.72-1.85 (m, 6H), 2.02-2.08 (m, 1H), 2.16-2.25 (m, 1H), 2.58-2.66(m, 1H), 3.52-3.63 (m, 1H).

Synthesis of 16.5

To a suspension of Ph₃PEtBr (29.1 g, 78.6 mmol) in anhydrous THF (25 mL)was added t-BuOK (8.8 g, 78.6 mmol) at 25° C. under N₂. After stirringat 45° C. for 30 min, a solution of 16.4 (4 g, 13.1 mmol) in anhydrousTHF (25 mL) was dropwise. After stirring for 12 h, the reaction mixturewas combined with another batch prepared from 4 g of 16.4. The combinedmixture was cooled and poured into ice-water (600 mL) stirred for 10min. The aqueous phase was extracted with EtOAc (2×400 mL). The combineorganic phase was washed with brine (2×400 mL), filtered andconcentrated. The residue was purified by flash column (0˜30% of EtOAcin PE) to give 16.5 (9 g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)0.57-0.72 (m, 1H), 0.57-0.73 (m, 1H), 0.77-0.80 (m, 3H), 0.90-0.96 (m,3H), 0.97-1.01 (m, 1H), 1.03-1.09 (m, 3H), 1.16-1.42 (m, 6H), 1.53-1.62(m, 5H), 1.66-1.75 (m, 4H), 1.80-1.90 (m, 3H), 1.92-2.04 (m, 1H),2.11-2.33 (m, 2H), 2.45-2.54 (m, 1H), 3.44-3.66 (m, 1H), 5.08-5.23 (m,1H).

Synthesis of 16.6

To a solution of 16.5 (9 g, 28.4 mmol) in DCM (100 mL) was added DMP (24g, 56.8 mmol). After stirring at 25° C. for 2 h, the mixture wasquenched with saturated NaHCO₃ aqueous (50 mL) at 10° C. The DCM phasewas separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1,2×100 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified with MeCN (210 mL) at82° C. to give 16.6 (8 g, 89.5%) as a solid. ¹H NMR (400 MHz, CDCl₃) δppm 0.69-0.92 (m, 3H), 0.94 (s, 1H), 0.97-1.01 (m, 3H), 1.05-1.19 (m,4H), 1.31-1.48 (m, 5H), 1.55-1.61 (m, 2H), 1.64-1.76 (m, 3H), 1.80-2.12(m, 5H), 2.13-2.46 (m, 4H), 2.46-2.55 (m, 1H), 2.82 (dd, J=16.44, 2.13Hz, 1H), 3.27 (br d, J=16.56 Hz, 1H), 5.10-5.24 (m, 1H).

Synthesis of 16.7

To a stirred solution of trimethylsulfoxonium iodide (11.1 g, 50.8 mmol)in DMSO (100 mL) was added t-BuOK (7.12 g, 63.5 mmol). After stirring at25° C. for 1.0 h under N₂, 16.6 (8 g, 25.4 mmol) was added. Afterstirring at 60° C. for 12 h, the reaction was diluted with water (100mL) and extracted with EtOAc (2×100 mL). The combined organic phase waswashed with water (2×100 mL), brine (30 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash column (PE/EtOAc=0˜30%) to afford 16.7 (4 g,47.9%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.81-0.84 (m, 4H), 0.93(s, 2H), 0.95-0.98 (m, 1H), 1.03-1.07 (m, 2H), 1.22-1.38 (m, 8H),1.38-1.46 (m, 2H), 1.62-1.69 (m, 2H), 1.70-1.78 (m, 4H), 1.79-1.94 (m,4H), 1.98-2.09 (m, 2H), 2.11-2.23 (m, 1H), 2.46-2.54 (m, 1H), 2.59-2.64(m, 2H), 5.11-5.21 (m, 1H).

Synthesis of 16.8

To a solution of 16.7 (4 g, 12.1 mmol) in THF (50 mL) was added CuI(1.15 g, 6.05 mmol), then EtMgBr (12.1 mL, 3 M, 36.3 mmol) at 0° C.After stirring at 0° C. for 1 h, the mixture was poured into water (200mL) and extracted with EtOAc (2×100 mL). The combined organic phase waswashed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 16.8 (3.2 g, 73.9%) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H) 0.69-0.74 (m, 3H), 0.77-0.83 (m, 1H), 0.87-0.95 (m, 5H),1.02-1.17 (m, 5H), 1.18-1.32 (m, 8H), 1.38 (br d, J=3.26 Hz, 4H),1.48-1.54 (m, 1H), 1.58 (br t, J=2.64 Hz, 5H), 1.62-1.70 (m, 3H),1.71-1.77 (m, 2H), 1.79-1.94 (m, 2H), 2.10-2.26 (m, 1H), 2.49 (br d,J=14.05 Hz, 1H), 5.10-5.20 (m, 1H).

Synthesis of 16.9

To a solution of 16.8 (3.2 g, 8.92 mmol) in THF (30 ml) was addedBH₃.Me₂S (2.67 ml, 26.7 mmol) at 25° C. After stirring at 45° C. for 2h, the reaction mixture was cooled and quenched by EtOH (4.10 g, 89.2mmol, 0.789 g/ml) at 0° C. and then NaOH (1.78 mL, 5M, 8.92 mmol) H₂O₂(10.1 g, 89.2 mmol, 1.13 g/mL, 30% in water) was added slowly until theinner temperature no longer rises and the inner temperature wasmaintained below 30° C. After stirring at 60° C. for 1 h, the reactionwas quenched with saturated aqueous Na₂S₂O₃ (100 mL) and stirred at 0°C. for 1 hour. The reaction was checked by potassium iodide-starch testpaper to confirm excess H₂O₂ was destroyed (did not changed to blue).The aqueous phase was extracted with DCM (3×100 mL). The combine organicphase was washed with saturated Na₂S₂O₃ (2×100 mL), brine (2×100 mL),dried over anhydrous Na₂SO₄ filtered and concentrated to give 16.9 (3.5g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.61-0.66 (m, 3H), 0.70 (s,1H), 0.68-0.72 (m, 1H), 0.72-0.78 (m, 2H), 0.81-0.89 (m, 5H), 0.90 (s,1H), 0.93-1.01 (m, 1H), 1.03 (d, J=6.27 Hz, 1H), 1.09 (br d, J=6.53 Hz,2H), 1.13-1.25 (m, 9H), 1.26 (br s, 1H), 1.31 (br d, J=3.01 Hz, 4H),1.39 (br d, J=3.76 Hz, 2H), 1.45 (br d, J=11.29 Hz, 2H), 1.47-1.64 (m,6H), 1.71-1.87 (m, 2H), 2.55 (s, 1H).

Synthesis of 16.10

To a solution of 16.9 (3.5 g, 9.29 mmol) in DCM (100 mL) at 25° C. wasadded silica gel (3.98 g) and PCC (3.98 g, 18.5 mmol). After stirring at25° C. for 2 h, the resulting mixture was filtered through a pad ofsilica gel and the filter cake was washed with DCM (40 mL×5). Thecombined filtrates were concentrated to give 16.10 (2.5 g, 71.8%) as anoil. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.63 (d, J=1.00 Hz, 3H), 0.69-0.81(m, 3H), 0.85 (br d, J=0.75 Hz, 6H), 1.01-1.11 (m, 2H), 1.19 (t, J=7.15Hz, 5H), 1.29-1.33 (m, 4H), 1.35-1.49 (m, 7H), 1.54 (s, 3H), 1.56-1.81(m, 4H), 2.06 (d, J=5.27 Hz, 3H), 2.22 (dd, J=12.80, 3.26 Hz, 1H), 2.39(d, J=5.27 Hz, 1H).

Synthesis of 16.10a & 16.10b

To a solution of 16.10 (250 mg, 0.667 mmol) in MeOH (10 mL, 0.667 mmol)was added methoxysodium (718 mg, 13.3 mmol) in one portion. Afterstirring at 70° C. for 12 h, the mixture was cooled and concentrated inreduced pressure at 25° C. The residue was poured into ice-water (20 mL)and stirred for 20 min. The aqueous phase was extracted with EtOAc (3×40mL). The combined organic phase was washed with brine (2×20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by pre-HPLC (Column: Welch Xtimate C18 150*25 mm*5 um;Condition: water (0.225% FA)-ACN; Begin B: 80%; End B: 100%) to afford16.10a (22 mg, 8.8%) and 16.10b (6.1 mg, 2.44%) as solids.

16.10: ¹H NMR (400 MHz, CDaCl₃) δ_(H) 0.72 (s, 3H), 0.76-0.88 (m, 3H),0.90-1.01 (m, 7H), 1.13-1.20 (m, 1H), 1.22 (br d, J=4.02 Hz, 1H),1.23-1.26 (m, 3H), 1.28 (br s, 1H), 1.29-1.33 (m, 2H), 1.38-1.44 (m,5H), 1.45-1.62 (m, 9H), 1.65-1.79 (m, 1H), 1.80-1.90 (m, 2H), 2.16 (s,3H), 2.31 (dd, J=12.67, 3.14 Hz, 1H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₅H₄₁O₁[M−H₂O+H]⁺ 357.3 found 357.3.

16.10b: ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.67-0.72 (m, 4H), 0.78-0.86 (m,2H), 0.88-0.95 (m, 8H), 1.08-1.16 (m, 2H), 1.17-1.24 (m, 5H), 1.24-1.31(m, 5H), 1.36-1.38 (m, 4H), 1.41-1.46 (m, 4H), 1.51 (br d, J=3.76 Hz,2H), 1.66-1.88 (m, 2H), 2.12 (s, 3H), 2.46 (d, J=5.27 Hz, 1H).LC-ELSD/MS purity 98%, MS ESI calcd. for C₂₅H₄₁O₁[M−H₂O+H]⁺ 357.3 found357.3.

Synthesis of 16.11

To a stirred solution of trimethylsulfanium (108 mg, 0.532 mmol) in DMSO(5 mL) was added NaH (21.1 mg, 0.532 mmol) at 25° C. After stirring for1.0 h under N₂. 16.10a (100 mg, 0.266 mmol) was added. After stirring at60° C. for 12 h, the mixture was poured into water (10 mL), stirred for20 min, and extracted with EtOAc (3×10 mL). The combined organic phasewas washed with brine (2×10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give 16.11 (180 mg) as an oil. The residue waspurified by flash column (0˜30% of EtOAc in PE) to give 16.12 (60 mg) asa solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.71 (s, 3H), 0.74-0.84 (m, 4H),0.85-0.97 (m, 8H), 1.13 (br d, J=12.55 Hz, 3H), 1.22 (s, 5H), 1.27-1.34(m, 3H), 1.38 (br d, J=3.51 Hz, 4H), 1.41-1.53 (m, 5H), 1.59-1.69 (m,1H), 1.73 (br d, J=12.55 Hz, 1H), 1.70-1.77 (m, 1H), 1.82 (br s, 2H),1.91-1.98 (m, 1H), 2.37 (s, 1H), 2.63 (d, J=4.77 Hz, 1H), 2.70-2.73 (m,1H).

Synthesis of 16 & 17

To a solution of 16.11 (60 mg, 0.154 mmol) in DMF (3 mL) was added1H-pyrazole-4-carbonitrile (28.6 mg, 0.308 mmol) and Cs₂CO₃ (100 mg,0.308 mmol) at 20° C. After stirring at 130° C. for 12 h, the mixturewas diluted with water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was separated, concentrated to give mixture ofdiastereomers 16 & 17 (30 mg) as a solid. The diastereomers wereseparated by SFC (Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um);Condition: 0.1% NH₃H₂O IPA; Begin B: 60%; End B: 60%) to afford 16 (5.1mg, 17.0%) and 17 (2.6 mg, 8.369%) as solids.

16: ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.68 (s, 3H), 0.73-0.94 (m, 7H), 0.99(s, 3H), 1.06-1.28 (m, 14H), 1.35-1.52 (m, 11H), 1.66 (br d, J=16.06 Hz,1H), 1.80 (br t, J=13.80 Hz, 2H), 2.37 (br d, J=12.05 Hz, 1H), 2.98 (s,1H), 3.92-4.32 (m, 2H), 7.86 (d, J=19.58 Hz, 2H). LC-ELSD/MS purity 99%,MS ESI calcd. for C₃₀H₄₄N₃ [M−2H₂O+H]⁺ 446.4 found 446.4. SFC 100% de.

17: ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.63 (s, 3H), 0.69-0.86 (m, 7H), 0.88(s, 3H), 0.92 (s, 3H), 1.01-1.24 (m, 11H), 1.27-1.42 (m, 10H), 1.61-1.84(m, 4H), 2.25 (br d, J=12.55 Hz, 1H), 2.38 (s, 1H), 4.11-4.34 (m, 2H),7.64-7.91 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₃₀H₄₄N₃[M−2H₂O+H]⁺ 446.3 found 446.3.

Example 18 & 19:1-((S)-2-hydroxy-2-((1S,3aS,3bS,8S,10aR,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyl-1,2,3,3a,3b,4,6,7,8,9,10,10a,10b,11,12,12a-hexadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(18) &1-((R)-2-hydroxy-2-((1S,3aS,3bS,8S,10aR,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyl-1,2,3,3a,3b,4,6,7,8,9,10,10a,10b,11,12,12a-hexadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(19)

Synthesis of 18.2

To a solution of 18.1 (50.0 g, 157 mmol) in toluene (500 mL) was addedpyridine.HCl (3.61 g, 31.4 mmol) and ethane-1,2-diol (48.7 g, 785 mmol).The mixture was stirred at 135° C. for 48 hrs to remove water byDean-Stark trap. The mixture was concentrated under reduced pressure.The residue was triturated from EtOAc (150 mL) to give the product 18.2(35.0 g, 62%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.35 (d, J=5.2 Hz, 1H),4.03-3.83 (m, 4H), 3.58-3.47 (m, 1H), 2.34-2.17 (m, 2H), 2.10-1.92 (m,2H), 1.88-1.61 (m, 6H), 1.53-1.43 (m, 5H), 1.30 (s, 3H), 1.23-1.06 (m,3H), 1.01 (s, 3H), 0.96-0.84 (m, 3H), 0.78 (s, 3H).

Synthesis of 18.3

To a solution of 18.2 (10.0 g, 27.7 mmol) in DCM (200 mL) was addedDess-Martin reagent (35.2 g, 83.1 mmol). The reaction mixture wasstirred at 20° C. for 1 hr. The reaction mixture was quenched withsaturated NaHCO₃ (500 mL) and saturated Na₂S₂O₃ (200 mL) at 0° C. andstirred for 20 min. The mixture was extracted with DCM (2×200 mL). Thecombined organic layer was washed with saturated NaHCO₃ (2×200 mL) andsaturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the product 18.3 (11.0 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 5.40-5.30 (m, 1H), 4.02-3.87 (m, 4H), 3.28 (d, J=16.4 Hz, 1H),2.82 (dd, J=2.0, 16.4 Hz, 1H), 2.53-2.42 (m, 1H), 2.34-2.26 (m, 1H),2.13-1.99 (m, 3H), 1.85-1.68 (m, 4H), 1.55-1.42 (m, 4H), 1.31-1.24 (m,6H), 1.19 (s, 3H), 1.08-1.00 (m, 2H), 0.81 (s, 3H).

Synthesis of 18.4a and 18.4b

A cold (−70° C.) LDA solution (139 mL, 1.0 M, 139 mmol, fresh prepared)was added to a stirred solution of 18.3 (10.0 g, 27.8 mmol) and ethyldiazoacetate (15.8 g, 139 mmol) in THF (160 mL) at −70° C. The mixturewas stirred at −70° C. for 2 h. Then acetic acid (8.34 g, 139 mmol) inTHF (40 mL) was added, the mixture was then warmed to 20° C. and stirredfor 16 hrs. Water (300 mL) and PE (200 mL) was added, the organic phasewas separated and the aqueous phase was extracted with EtOAc (150 mL).The combined organic layers were washed with saturated brine (200 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give theproduct (13 g), which was used directly in next step. To a solution ofthe product (12 g, 25.3 mmol) in DME (100 mL) was added Rh₂(OAc)₄ (335mg, 0.76 mmol). The reaction mixture was stirred at 25° C. for 16 hrs togive a solution. The reaction mixture was concentrated. The residue waspurified by silica gel chromatography (0-20% of EtOAc in PE) to give themixture product 18.4a and 18.4b (6.80 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)12.8-12.6 (m, 0.2H), 5.69-5.44 (m, 1H), 4.29-4.10 (m, 2H), 4.04-3.82 (m,4H), 3.44-3.17 (m, 0.8H), 2.99-2.65 (m, 1H), 2.48-1.96 (m, 4H),1.85-1.61 (m, 6H), 1.55-1.40 (m, 3H), 1.34-1.14 (m, 12H), 1.02-0.96 (m,3H), 0.79 (s, 3H).

Synthesis of 18.5a and 18.5b

To a mixture of 18.4a and 18.4b (6.80 g, 15.2 mmol) in MeOH (150 mL) wasadded H₂O (50 mL) and NaOH (6.08 g, 152 mmol). The reaction mixture wasstirred at 60° C. for 16 hrs to give a mixture. The reaction mixture wasconcentrated. Then H₂O (150 mL) was added. The mixture was extractedwith EtOAc (3×150 mL). The combined organic phase was washed withsaturated brine (150 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(0-2% of EtOAc in DCM) to give the product 18.5a (1.5 g, 26%) and theproduct 18.5b (900 mg, 16%).

18.5a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.57 (d, J=4.4 Hz, 1H), 4.04-3.82(m, 4H), 2.67-2.56 (m, 1H), 2.49-2.25 (m, 4H), 2.20-1.97 (m, 3H),1.84-1.59 (m, 7H), 1.56-1.37 (m, 3H), 1.30 (s, 3H), 1.26-1.03 (m, 4H),1.00 (s, 3H), 0.79 (s, 3H).

18.5b: ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.56 (d, J=4.4 Hz, 1H), 4.05-3.83(m, 4H), 3.25 (d, J=14.0 Hz, 1H), 2.82 (d, J=14.4 Hz, 1H), 2.65-2.53 (m,1H), 2.24-2.01 (m, 3H), 1.89-1.60 (m, 7H), 1.57-1.39 (m, 4H), 1.30 (s,3H), 1.28-1.02 (m, 5H), 0.99 (s, 3H), 0.79 (s, 3H).

Synthesis of 18.6

To a solution of BHT (10.6 g, 48.3 mmol) in toluene (100 mL) undernitrogen at 0° C. was added trimethylaluminum (2 M in toluene, 12.0 mL,24.1 mmol) dropwise. The mixture was stirred at 25° C. for 1 h and useddirectly as a solution of MAD without further purification. To the MADsolution was added a solution of 18.5a (3.0 g, 8.0 mmol) in anhydrousDCM (20 mL) drop-wise at −70° C. After stirring at −70° C. for 1 h underN₂, MeMgBr (8.03 mL, 24.1 mmol, 3M in ethyl ether) was added dropwise at−70° C. The resulting solution was stirred at −70° C. for another 2 h.The reaction mixture was poured into saturated aqueous citric acid (100mL) below 10° C. and extracted with EtOAc (2×30 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give product. The product was purifiedtogether with another batch (from 300 mg of 18.5a). The residue wastriturated from PE (20 mL) at 20° C. to give 18.6 (3.3 g), which wasused without further purification and used directly for the next step.

Synthesis of 18.7

To a solution of 18.6 (3.30 g, 8.5 mmol) in THF (50 mL) was added 12MHCl (3 mL, 36.0 mmol). The reaction mixture was stirred at 20° C. for 16hours to give a solution. The reaction mixture was diluted with H₂O (50mL) and adjust to pH=9 with solid Na₂CO₃ (20 g). The product wasextracted with EtOAc (3×30 mL). The combined organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated to give the product.The product was purified by flash column (20˜100% of EtOAc in PE) toprovide 18.7 (600 mg) as a solid.

18.7: ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.40 (d, J=3.6 Hz, 1H), 2.53 (t,J=8.8 Hz, 1H), 2.28-2.17 (m, 2H), 2.12 (s, 3H), 2.10-2.01 (m, 2H),1.92-1.50 (m, 8H), 1.49-1.32 (m, 6H), 1.30-1.19 (m, 7H), 0.91 (s, 3H),0.63 (s, 3H).

Synthesis of 18.8

To a mixture of MePPh₃Br (7.75 g, 21.7 mol) in THF (30 mL) was addedt-BuOK (2.43 g, 21.7 mol) at 25° C. under N₂. The resulting mixture wasstirred at 50° C. for 30 min. Compound 18.7 (2.50 g, 7.25 mol) was addedin portions keeping the temperature below 50° C. The reaction mixturewas stirred at 60° C. for 16 hours to give a suspension. The reactionmixture was quenched with 10% NH₄Cl aqueous (50 mL) at 25° C. Theorganic layer was separated. The aqueous layer was extracted with EtOAc(50 mL×2). The combined organic phase was concentrated under reducedpressure to give a solid, which was purified by silica gelchromatography (0-50% of EtOAc in PE) to give 18.8 (2.50 g, 99%). ¹H NMR(400 MHz, CDCl₃) δ 5.50-5.41 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H),2.10-1.94 (m, 3H), 1.93-1.77 (m, 4H), 1.76 (s, 3H), 1.75-1.64 (m, 3H),1.63-1.56 (m, 2H), 1.55-1.31 (m, 6H), 1.31-1.26 (m, 2H), 1.25 (s, 3H),1.24-1.05 (m, 5H), 0.89 (s, 3H), 0.59 (s, 1H).

Synthesis of 18.9

To a solution 18.8 (300 mg, 0.875 mmol) in DCM (5 mL), was added m-CPBA(188 mg, 0.875 mmol). The resulting mixture was stirred at 20° C. for 2h. The mixture was quenched with saturated NaHCO₃ aqueous (100 mL) at20° C. The DCM phase was separated and washed with saturatedNaHCO₃/Na₂S₂O₃ aqueous (1:1, 2×100 mL), brine (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give 18.9(350 mg). ¹H NMR (400 MHz, CDCl₃) δ 5.46 (s, 1H), 4.85 (s, 1H), 4.70 (s,2H), 2.89 (d, J=4.4 Hz, 1H), 2.59-2.48 (m, 1H), 2.59-2.48 (m, 1H), 2.32(d, J=4.8 Hz, 1H), 2.26-2.17 (m, 2H), 2.00-1.79 (m, 6H), 1.70-1.64 (m,4H), 0.98 (s, 8H), 0.89 (s, 2H), 0.81 (s, 1H), 0.69 (s, 3H), 0.58 (s,5H).

Synthesis of 18 and 19

A solution of 18.9 (350 mg, 0.98 mmol), Cs₂CO₃ (957 mg, 2.92 mmol) and1H-pyrazole-4-carbonitrile (181 mg, 1.95 mmol) in DMF (10 mL) wasstirred at 120° C. for 16 hours. The mixture was added into saturatedNH₄Cl (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with LiCl (50 mL, 3% in water),saturated brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(0-20% of acetone in DCM) to yield 18.10 (70 mg) which was purified bySFC (Column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); Condition:0.1% NH₃H₂O EtOH; Begin B: 45%; End B: 45%; Gradient Time (min): n/a;100% B Hold Time (min): n/a; Flow Rate(ml/min); 70) to afford 18 (40.3mg, 57.6%) and 19 (17.3 mg, 24.7%).

18: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.82 (s, 1H), 5.46 (d, J=4.0Hz, 1H), 4.36 (d, J=13.6 Hz, 1H), 4.09 (d, J=13.6 Hz, 1H), 2.50 (s, 1H),2.11-1.94 (m, 3H), 1.93-1.84 (m, 2H), 1.82-1.63 (m, 4H), 1.61-1.55 (m,2H), 1.54-1.34 (m, 6H), 1.28-1.25 (m, 2H), 1.25 (s, 3H), 1.23-1.00 (m,4H), 0.98 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H). LCMS purity≥99%, MS ESIcalcd. for C₂₈H₃₈N₃ [M−2H₂O+H]⁺ 416.3, found 416.3.

19: ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.83 (s, 1H), 5.48 (d, J=4.0Hz, 1H), 4.23-4.16 (m, 1H), 4.07-4.00 (m, 1H), 2.31 (s, 1H), 2.16-1.85(m, 6H), 1.79-1.67 (m, 3H), 1.65-1.57 (m, 4H), 1.56-1.35 (m, 8H),1.32-1.28 (m, 2H), 1.27 (s, 3H), 1.26-1.13 (m, 4H), 1.13 (s, 3H),1.11-1.04 (m, 1H), 0.92 (d, J=2.4 Hz, 6H). LCMS purity≥99%, MS ESIcalcd. for C₂₈H₃₈N₃ [M−2H₂O+H]⁺ 416.3, found 416.3.

Example 20 & 21:1-((S)-2-hydroxy-2-((1S,3aS,3bR,5aR,7R,10aS,10bR,12aS)-7-hydroxy-7,12a-dimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(20) &1-((R)-2-hydroxy-2-((1S,3aS,3bR,5aR,7R,10aS,10bR,12aS)-7-hydroxy-7,12a-dimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(21)

Synthesis of 20.2

To a solution of 20.1 (10 g, 36.4 mmol) in THF (50 mL) was added Pd/C (1g, dry) and HBr (0.5 mL). The reaction mixture was degassed underreduced pressure and purged with H₂ for five times. The mixture wasstirred at 20° C. for 16 hrs under H₂. The reaction mixture was filteredthrough a pad of Celite and washed with THF (5×20 mL). The filtrate wasconcentrated. The residue was triturated from petroleum ether (10 mL) at20° C. to give 20.2 (10.31 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.75-3.65(m, 2H), 2.61-2.54 (m, 1H), 2.23-2.04 (m, 6H), 1.87-1.62 (m, 6H),1.52-1.46 (m, 3H), 1.29-1.07 (m, 7H), 0.77 (s, 3H).

Synthesis of 20.3

To a solution of diisopropylamine (27.9 g, 276 mmol) in anhydrous THF(110 mL) under nitrogen at −70° C. was added n-BuLi (2.5 M in hexane,110 mL, 276 mmol) dropwise. The mixture was stirred at −70° C. for 20min. To a solution of 20.2 (20 g, 55.4 mmol) in THF (600 mL) was addedethyl diazoacetate (31.4 g, 276 mmol) under N₂ atmosphere. Then thefreshly prepared LDA (276 mmol) was added dropwise at −70° C. Themixture was stirred at −70° C. for 4 hours. Then acetic acid (22.0 g,276 mmol) in THF (100 mL) was added to quench the reaction at −70° C.The mixture was then warmed to 25° C. and stirred for 12 h. Water (200mL) was added. The aqueous solution was extracted with EtOAc (2×600 mL).The combined organic layer was washed with brine (1000 mL), dried overNa₂SO₄, and concentrated to give 20.3 (40.0 g).

Synthesis of 20.4 & 20.4a

To a solution of 20.3 (30.0 g) in DME (300 mL) was added Rh₂(OAc)₄ (373mg, 0.84 mmol) at 25° C. The reaction mixture was stirred at 40° C. for12 hours. The reaction mixture was concentrated under reduced pressureto give 20.4 & 20.4a (30.0 g).

Synthesis of 20.5 & 20.5a

To a mixture of 20.4 & 20.4a (30.0 g, 82.7 mmol) in MeOH/THF/H₂O (200mL/200 mL/50 mL) was added NaOH (33.0 g, 827 mmol). The reaction mixturewas stirred at 70° C. for 12 hour. The reaction mixture was extractedwith ethyl acetate (2×500 mL). The combined organic phase was washedwith water (500 mL), brine (600 mL), dried over Na₂SO₄, filtered andconcentrated to give 20.5 & 20.5a (20.0 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 3.67 (br s, 1H), 3.05 (t, J=12.67 Hz, 1H), 2.37-2.52 (m, 2H),1.82-2.14 (m, 6H), 1.62-1.78 (m, 6H), 0.94-1.46 (m, 8H), 0.77 (s, 3H).

Synthesis of 20.6 & 20.6a

A solution of 20.5 & 20.5a (20.0 g, 68.8 mmol) in DCM (300 mL) was addedDMP (58 g, 137 mmol) under N₂. The reaction mixture was stirred at 15°C. under N₂ for 2 hrs to get a mixture. The mixture was poured intosaturated aqueous NaHCO₃ (500 mL), then saturated aqueous Na₂S₂O₃ (500mL) was added. The aqueous phase was extracted with DCM (3×200 mL). Thecombined organic phase was washed with brine (2×500 mL), dried overanhydrous Na₂SO₄, filtered, concentrated and purified by flash column(0˜20% of EtOAc in PE) to give 20.6 & 20.6a (14.5 g, 73.2%), which waspurified by SFC (Column DAICEL CHIRALPAK IC (250 mm*50 mm, 10 um)Condition 0.10%₀NH₃.H₂O ETOH Begin B 40% End B 40% Gradient Time (min)100% B Hold Time (min) Flow Rate(ml/min) 200 Injections 500) to afford20.6a (3.8 g) as solid and 20.6 (9 g) as solid, which was re-purified byflash column (0˜30% of EtOAc in PE) to give 20.6 (3.5 g, 24.3%). The20.6a was purified by flash column (0˜20% of EtOAc in PE) to give 20.6a(3.5 g, 13.1 mmol).

20.6: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.04 (t, J=12.55 Hz, 1H), 2.35-2.55(m, 3H), 1.91-2.17 (m, 5H), 1.50-1.88 (m, 10H), 0.99-1.45 (m, 7H), 0.90(s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C19H29O2 [M+H]+ 289.3found 289.3.

20.6a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.24-2.63 (m, 5H), 1.88-2.17 (m,5H), 1.63-1.86 (m, 6H), 1.06-1.60 (m, 10H), 0.90 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₁₉H₂₉O₂ [M+H]⁺ 289.3 found 289.3.

Synthesis of 20.7

To a solution of 2,6-di-tert-butyl-4-methylphenol (15.9 g, 72.6 mmol) intoluene (40 mL) was added dropwise AlMe₃ (18.1 mL, 36.3 mmol, 2 M intoluene) at 0° C. The mixture was stirred at 25° C. for 30 min. Asolution of 20.6 (3.5 g, 12.1 mmol) in anhydrous DCM (5 mL) was addeddropwise to MAD (36.3 mmol) solution at −70° C. After stirring at −70°C. for 1 h, MeMgBr (12.1 mL, 36.3 mmol, 3 M in ethyl ether) was addeddropwise at −70° C. and stirred at −70° C. for 1 h. The reaction mixturewas poured into saturated aqueous citric acid (50 mL) below 10° C. Theaqueous solution extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (80 mL), dried by Na₂SO₄, and evaporatedunder reduced pressure to give the product. The product was purified byflash column (10˜30% of EtOAc in PE) to give 20.7 (1.8 g). Compound 20.7(200 mg) was purified by flash column (0˜30% of EtOAc in PE) to give20.7 (14.3 mg).

20.7: ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.44 (dd, J=19.20, 8.16 Hz, 1H),1.75-2.16 (m, 8H), 1.58-1.66 (m, 2H), 1.41-1.53 (m, 4H), 0.95-1.40 (m,13H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₀H₃₁O[M−H₂O+H]⁺ 287.3 found 287.3.

Synthesis of 20.8

To a solution of t-BuOK (2.19 g, 19.6 mmol) in THF (20 mL) was addedEtPPh₃Br (7.27 g, 19.6 mmol) at 40° C. under N₂. The mixture was stirredat 40° C. for 30 min to give solution. Then compound 20.7 (2.0 g, 6.56mmol) in THF (10 ml) was added. The mixture was stirred at 40° C. for 30min to give solution. The mixture was poured into water (30 mL) andstirred for 20 min. The aqueous phase was extracted with EtOAc (3×40mL). The combined organic phase was washed with brine (2×30 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash column (0-10% of EtOAc in PE) to give 20.8 (1.6.0 g,77.2%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.05-5.24 (m, 1H), 1.95-2.43 (m,5H), 1.61-1.94 (m, 8H), 1.15-1.53 (m, 15H), 0.92-1.14 (m, 4H), 0.89 (s,3H).

Synthesis of 20.9

To a solution of 20.8 (1.6 g, 5.05 mmol) in THF (30 mL) was added 9-BBNdimer (2.44 g, 10.1 mmol) under N₂. The reaction mixture was stirred at50° C. under N₂ for 2 hrs to get a mixture and cooled to 0° C. To thereaction mixture was added ethanol (4.40 mL, 75.7 mmol) and NaOH (15.1mL, 5 M, 75.7 mmol). Subsequently, H₂O₂ (8.56 g, 30%, 75.7 mmol) wasadded dropwise at 15° C. The mixture was stirred at 50° C. for 2 hours.Saturated aqueous Na₂S₂O₃ (50 mL) was added and the mixture was stirredat 0° C. for another 1 hour. The reaction was checked by potassiumiodide-starch test paper to confirm excess H₂O₂ was destroyed. Theaqueous phase was extracted with EtOAc (3×40 mL). The combined organicphase was washed with brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give 20.9 (1.0 g).

Synthesis of 20.10

To a solution of 20.9 (1.0 g, 2.98 mmol) in DCM (30 mL) was added DMP(1.44 g, 5.96 mmol) under N₂. The reaction mixture was stirred at 15° C.under N₂ for 2 hrs to get a mixture. The mixture was added saturatedaqueous NaHCO₃ (50 mL) and saturated aqueous Na₂S₂O₃ (50 mL) was added.The aqueous phase was extracted with DCM (3×40 mL). The combined organicphase was washed with brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered, concentrated and purified by flash column (0˜20% of EtOAc inPE) to give 20.10 (0.8 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.55 (t,J=8.91 Hz, 1H), 2.16 (br d, J=9.29 Hz, 1H), 2.12 (s, 3H), 1.95-2.05 (m,2H), 1.71-1.92 (m, 4H), 1.37-1.70 (m, 10H), 0.87-1.35 (m, 13H), 0.63 (s,3H).

Synthesis of 20.11

To a solution of t-BuOK (1.0 g, 9.00 mmol) in THF (20 mL) was addedMePPh₃Br (3.21 g, 9.00 mmol) at 50° C. under N₂. The mixture was stirredat 50° C. for 30 min to give solution. 20.10 (1.0 g, 3.00 mmol) in THF(10 ml) was added. The mixture was stirred at 50° C. for 30 min to givesolution. The mixture was poured into water (30 mL) and stirred for 20min. The aqueous phase was extracted with EtOAc (3×40 mL). The combinedorganic phase was washed with brine (2×20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashcolumn (0-10% of EtOAc in PE) to give 20.11 (800 mg, 80.7%). ¹H NMR (400MHz, CDCl₃) δ_(H) 4.85 (s, 1H), 4.71 (s, 1H), 1.77-2.05 (m, 6H),1.62-1.71 (m, 3H), 1.35-1.60 (m, 9H), 1.08-1.33 (m, 12H), 0.83-1.03 (m,4H), 0.58 (s, 3H).

Synthesis of 20.12

To a solution of 20.11 (150 mg, 0.4537 mmol) in DCM (10 mL) was addedm-CPBA (156 mg, 0.9074 mmol, 80%) at 0° C. The solution was stirred at25° C. for 1 h to give a suspension. The mixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, 1:1) and extracted with DCM (3×20 mL). Thecombined organic phase was washed with sat. NaHCO₃ and Na₂S₂O₃ (60 mL,1:1), dried over Na₂SO₄, filtered and concentrated to give 20.12 (220mg).

Synthesis of 20 and 21

A mixture of 20.12 (220 mg, 0.6348 mmol), Cs₂CO₃ (619 mg, 1.90 mmol) and1H-pyrazole-4-carbonitrile (117 mg, 1.26 mmol) in DMF (10 mL) wasstirred at 130° C. for 12 hours to give a suspension. The mixture waspoured into saturated NH₄Cl (50 mL). The aqueous layer was extractedwith EtOAc (3×50 mL). The combined organic layer was washed with LiCl(50 mL, 5% in water), brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered, concentrated and purified by column (0˜50% of EtOAc in PE) toafford 20 & 21 (300 mg). The diastereomers were purified by SFC (ColumnDAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um) Condition 0.10% NH₃H₂O ETOHBegin B 40 End B 40 Gradient Time (min) 100% B Hold Time (min) Flow Rate(ml/min) 60) to afford 21 (51.2 mg, 16%, Rt=4.210 min) as a solid and 20(124.2 mg, 39.8%, Rt=4.855 min).

21: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (s, 1H), 7.81 (s, 1H), 4.11-4.25(m, 1H), 3.93-4.08 (m, 1H), 2.29 (s, 1H), 1.75-2.11 (m, 6H), 1.64-1.72(m, 3H), 1.35-1.52 (m, 5H), 0.93-1.31 (m, 13H), 0.89 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M−2H₂O+H]⁺ 404.3 found 404.3.SFC 100% de.

20: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.94 (s, 1H), 7.82 (s, 1H), 4.36 (d,J=13.76 Hz, 1H), 4.09 (d, J=13.76 Hz, 1H), 2.49 (s, 1H), 1.93-2.06 (m,2H), 1.62-1.90 (m, 7H), 1.36-1.57 (m, 9H), 1.01-1.33 (m, 12H), 0.98 (s,3H), 0.94 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃[M−2H₂O+H]⁺ 404.3 found 404.3. SFC 100% de.

Example 22 & 23:1-((S)-2-hydroxy-2-((1S,3aS,3bR,5aS,8S,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(22) &1-((R)-2-hydroxy-2-((1S,3aS,3bR,5aS,8S,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrocyclohepta[a]cyclopenta[f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(23)

Synthesis of 22.2

To a solution of 22.1 (13 g, 41.3 mmol) in THF (400 mL) was added ethyldiazoacetate (23.5 g, 206 mmol) under N₂ followed by LDA (206 mmol) at−70° C. After stirring at −70° C. for 4 h, a solution of acetic acid(16.4 g, 206 mmol) in THF (100 mL) was added to quench the reaction at−70° C. The mixture was then warmed to 25° C. stirred for 12 h andtreated with water (200 mL). The aqueous solution was extracted withdiethyl ether (2×300 mL). The combined organic layer was washed withbrine (300 mL), dried over Na₂SO₄, and concentrated to give 22.2 (17 g).¹H NMR (400 MHz, CDCl₃) δ_(H) 4.88-4.79 (m, 1H), 4.75-4.67 (m, 1H),4.37-4.19 (m, 4H), 3.52-3.28 (m, 1H), 2.01-1.82 (m, 3H), 1.75 (s, 11H),1.47-1.31 (m, 7H), 0.99-0.63 (m, 7H), 0.55 (s, 3H).

Synthesis of 22.3 & 22.3a

To a solution of 22.2 (17 g, 41.0 mmol) in DME (50 mL) was addedRh₂(OAc)₄ (271 mg, 0.615 mmol) at 25° C. The reaction mixture wasstirred at 40° C. for 2 hours. The reaction mixture was extracted withethyl acetate (3×20 mL). The combined organic phase was washed withwater (30 mL), brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 22.3 & 22.3a (16 g).

Synthesis of 22.4 & 22.4a

To a mixture of 22.3 & 22.3a (16 g, 5.54 mmol) in MeOH/THF/H₂O (200mL/100 mL/50 mL) was added NaOH (15.9 g, 399 mmol). The reaction mixturewas stirred at 70° C. for 12 hour. The reaction mixture was extractedwith ethyl acetate (4×500 mL). The combined organic phase was washedwith water (500 mL), brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the product, which waspurified by flash column (0-10% of EtOAc in PE) to give 22.4 & 22.4a (13g). The mixture of 22.4 & 22.4a was purified by SFC (Column: DAICELCHIRALPAK AD (250 mm*50 mm, 10 um); Condition: 0.1% NH₃H₂O ETOH; Begin B30% End B 30%; Flow Rate (ml/min): 200) to give 22.4 (3.3 g) and 22.4a(3.0 g).

22.4: ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H),2.63-2.39 (m, 3H), 2.35-2.26 (m, 1H), 2.06-1.95 (m, 2H), 1.75 (s, 10H),1.41-1.10 (m, 10H), 0.98-0.86 (m, 1H), 0.81 (s, 4H), 0.56 (s, 3H).LC-ELSD/MS purity 99%, MS ESI calcd for C₂₃H₃₇O [M+H]⁺ 329.3, found329.3, C₂₃H₃₅ [M−H₂O+H]⁺ 311.3, found 311.3.

22.4a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H), 2.81(dd, J=11.2, 15.2 Hz, 1H), 2.53-2.30 (m, 2H), 2.12-1.90 (m, 3H),1.89-1.81 (m, 1H), 1.75 (s, 10H), 1.49-1.00 (m, 9H), 0.88 (s, 4H),0.82-0.73 (m, 1H), 0.56 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd forC₂₃H₃₇O [M+H]⁺ 329.3, found 329.3, C₂₃H₃₅ [M−H₂O+H]⁺ 311.3, found 311.3.

Synthesis of 22.5

To a solution of 2,6-di-tert-butyl-4-methylphenol (12.8 g, 58.4 mmol) intoluene (40 mL) was added dropwise AlMe₃ (14.6 mL, 29.2 mmol, 2 M intoluene) at 0° C. The mixture was stirred at 25° C. for 30 min and usedas a MAD solution. To a solution of 22.4 (3.2 g, 9.74 mmol) in anhydrousDCM (20 mL) was added dropwise to a MAD (29.2 mmol) solution at −70° C.After stirring at −70° C. for 1 h, MeMgBr (9.73 mL, 29.2 mmol, 3M inethyl ether) was added dropwise at −70° C. and stirred at −70° C. for 1h. The reaction mixture was poured into saturated aqueous citric acid(15 mL) below 10° C. The aqueous solution was extracted with EtOAc(3×100 mL). The combined organic layer was washed with brine (200 mL),dried by Na₂SO₄, and evaporated under reduced pressure to give theproduct. The product was purified by flash column (10˜30% of EtOAc inPE) to give 22.4 (1.1 g, recovered) and 22.5 (2.0 g). ¹H NMR (400 MHz,CDCl₃) δ_(H) 4.90-4.78 (m, 1H), 4.74-4.65 (m, 1H), 2.07-1.96 (m, 1H),1.75 (s, 13H), 1.46-1.24 (m, 5H), 1.20 (s, 11H), 0.82-0.79 (m, 1H), 0.75(s, 3H), 0.55 (s, 3H).

Synthesis of 22.6

To a solution of 22.5 (300 mg, 0.87 mmol) in DCM (6 mL) was added m-CPBA(352 mg, 85%, 1.74 mmol) at 15° C. After stirring at 15° C. for 1 hourto give a solution, the mixture was quenched with saturated NaHCO₃aqueous (10 mL) at 15° C. The DCM phase was separated and washed withsaturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 2×10 mL), brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give22.6 (300 mg).

Synthesis of 22 & 23

A solution of 22.6 (300 mg, 0.8319 mmol), Cs₂CO₃ (811 mg, 2.49 mmol) and1H-pyrazole-4-carbonitrile (154 mg, 1.66 mmol) in DMF (10 mL) wasstirred at 130° C. for 12 hours to give a solution. The mixture waspoured into saturated NH₄Cl (50 mL). The aqueous layer was extractedwith EtOAc (3×50 mL). The combined organic layer was washed with LiCl(100 mL, 5% in water), brine (2×100 mL), dried over anhydrous Na₂SO₄,filtered, concentrated and purified by column (0˜30% of EtOAc in PE) toafford 22 & 23 (260 mg).

22 & 23 (260 mg) was purified by SFC (Column: DAICEL CHIRALPAK AD (250mm*30 mm, 10 um); Condition: 0.1% NH₃H₂O IPA; Begin B 50% End B 50%;Flow Rate (ml/min) 70) to afford 23 (50.6 mg, 19.5%, Rt=1.627 min) and22 (72.4 mg, 27.9%, Rt=1.247 min).

22: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.35 (d,J=14.0 Hz, 1H), 4.08 (d, J=13.6 Hz, 1H), 2.48 (s, 1H), 2.05-1.97 (m,1H), 1.92-1.81 (m, 1H), 1.80-1.56 (m, 8H), 1.44-1.24 (m, 7H), 1.22-0.87(m, 17H), 0.76 (s, 4H). LC-ELSD/MS purity 99%, MS ESI calcd forC₂₈H₄₀N₃O₂ [M−2H₂O+H]⁺ 418.3, found 418.3. SFC 100% de.

23: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.80 (s, 1H), 4.20-4.11(m, 1H), 4.04-3.97 (m, 1H), 2.27 (s, 1H), 2.08-1.99 (m, 1H), 1.96-1.82(m, 2H), 1.75-1.56 (m, 7H), 1.20 (s, 16H), 1.09 (s, 4H), 0.86 (s, 4H),0.76 (s, 4H). LC-ELSD/MS purity 99%, MS ESI calcd for C₂₈H₄₀N₃O₂[M−2H₂O+H]⁺ 418.3, found 418.3. SFC 99% de.

Example 24 & 25:1-((R)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,8,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(24) &1-((S)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,8,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(25)

Synthesis of 24.2

To a solution of t-BuOK (3.86 g, 34.4 mmol) in THF (110 mL) was added24.1 (5.0 g, 17.2 mmol) at 25° C. under N₂. The mixture was stirred at25° C. for 10 min. Then methyl benzenesulfinate (5.37 g, 34.4 mmol) wasadded. The mixture was stirred at 30° C. for 0.5 h. The mixture wasquenched with H₂O (200 mL) and extracted with EtOAc (200×3 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 24.2 (8.7 g). ¹H NMR (400MHz, CDCl₃) δ_(H) 7.70-7.45 (m, 10H), 3.52-3.42 (m, 1H), 3.25 (t, J=11.6Hz, 1H), 2.43-2.29 (m, 1H), 1.86-1.75 (m, 7H), 1.64-1.58 (m, 3H),1.42-1.34 (m, 8H), 0.93 (s, 3H).

Synthesis of 24.3

To a mixture of 24.2 (8.7 g, 20.9 mmol) in xylene (110 mL) was addedNa₂CO₃ (33.1 g, 313 mmol) in portions. The reaction mixture was stirredat 130° C. for 12 hours under N₂. The mixture was filtered andconcentrated. The residue was purified by silica gel chromatography(0-15% of EtOAc in PE) to give the product 24.3 (3.7 g, 61.4%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 7.52 (d, J=6.0 Hz, 1H), 6.10-5.93 (m, 1H),2.41-2.30 (m, 1H), 1.90-1.67 (m, 7H), 1.62-1.48 (m, 4H), 1.45-1.37 (m,5H), 1.35-1.30 (m, 2H), 1.28 (s, 3H), 1.26-1.23 (m, 1H), 1.07 (s, 3H).

Synthesis of 24.4

To a solution of MeMgBr (17.0 mL, 51.2 mmol, 3M) in THF (30 mL) wasadded CuI (7.31 g, 38.4 mmol) at 0° C. and stirred at 0° C. for 1 hour,then 24.3 (3.7 g, 12.8 mmol) in THE (40 mL) was added at 0° C. Afterstirring at 0° C. for 3 hours, the mixture was poured into saturatedNH₄Cl (200 mL) and extracted with EtOAc (3×150 mL). The combined organiclayer was washed with brine (2×100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0%˜70% of EtOAc in PE) to give 24.4 (3.40 g, 87.4%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.54-2.36 (m, 2H), 2.30-2.18 (m, 1H), 1.93-1.79 (m, 3H),1.77-1.61 (m, 4H), 1.55-1.46 (m, 3H), 1.44-1.35 (m, 5H), 1.27 (s, 4H),1.10 (d, J=7.3 Hz, 3H), 1.03 (s, 3H), 0.93-0.80 (m, 4H).

Synthesis of 24.5

LDA (27.7 mL, 55.5 mmol) (2M in THF) was added to a stirred solution of24.4 (3.4 g, 11.1 mmol) and ethyl diazoacetate (7.03 g, 55.5 mmol, 90%)in THF (70 mL) at −70° C. The mixture was stirred at −70° C. for 2hours. Then acetic acid (3.17 mL, 55.5 mmol) in THE (30 mL) was addedand the mixture was warmed to 20° C. for 16 hours. Subsequently, water(300 mL) was added. The aqueous phase was extracted with EtOAc (3×100mL). The combined organic layer was washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give 24.5 (4.64 g).¹H NMR (400 MHz, CDCl₃) δ_(H) 7.79 (d, J 8.1 Hz, 2H), 7.35 (d, J=7.9 Hz,2H), 4.00-3.85 (m 2H), 2.46 (s, 3H), 1.91-1.59 (m, 7H), 1.50-1.29 (m,9H), 1.26 (s, 5H), 1.24-0.87 (m, 14H), 0.83 (t, J=6.7 Hz, 3H), 0.52 (s,3H).

Synthesis of 24.6

To a solution of 24.5 (6.64 g) in DME (100 mL) was added Rh₂(OAc)₄ (121mg, 0.275 mmol) in one portion at 20° C. The mixture was stirred at 20°C. for 16 hours. The mixture was treated with H₂O (200 mL). The mixturewas extracted with EtOAc (3×150 mL). The combined organic phase waswashed with brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 24.6 (4.29 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)4.23-4.19 (m, 2H), 2.30-2.16 (m, 2H), 1.93-1.64 (m, 8H), 1.62-1.51 (m,3H), 1.48-1.36 (m, 9H), 1.35-1.28 (m, 11H), 1.23 (s, 3H), 1.08 (d, J=7.3Hz, 3H), 1.04-0.94 (m, 2H), 0.84 (d, J=7.3 Hz, 2H).

Synthesis of 24.7

To a mixture of 24.6 (4.29 g) in MeOH (50 mL) was added H₂O (130 mL) andKOH (3.66 g, 65.3 mmol). The reaction mixture was stirred at 60° C. for2 hours to give a mixture. The reaction mixture was concentrated. ThenH₂O (200 mL) was added. The mixture was extracted with EtOAc (3×150 mL).The combined organic phase was washed with saturated brine (2×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (0-60% of EtOAc in PE) to give24.7 (2.0 g, 57.6%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.85-2.72 (m, 1H),2.22-2.10 (m, 2H), 1.90-1.82 (m, 3H), 1.80-1.70 (m, 4H), 1.68-1.53 (m,3H), 1.51-1.27 (m, 10H), 1.26 (s, 3H), 1.16 (s, 3H), 1.06 (d, J=7.2 Hz,3H), 1.03-0.95 (m, 1H)

Synthesis of 24.8

To a mixture of EtPPh₃Br (7.68 g, 20.7 mmol) in THF (50 mL) was addedt-BuOK (2.32 g, 20.7 mmol) at 20° C. under N₂. The resulting mixture wasstirred at 60° C. for 30 min. 24.7 (1.1 g) in THF (20 mL) was added inportions below 60° C. The reaction mixture was stirred at 60° C. for 16hours. The reaction mixture was quenched with 10% NH₄Cl aqueous (20 mL)at 15° C. The organic layer was separated. The aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic phase was washedwith brine (2×20 mL), filtered, concentrated under reduced pressure. Theresidue was purified by flash column (0˜5% ethyl acetate in PE) to give24.8 (1 g, 87.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.34-5.01 (m, 1H), 2.41(d, J=14.1 Hz, 1H), 2.34-1.96 (m, 3H), 1.94-1.85 (m, 1H), 1.82-1.69 (m,4H), 1.67-1.57 (m, 5H), 1.45-1.30 (m, 8H), 1.26 (s, 6H), 1.23-1.04 (m,4H), 1.01 (s, 3H), 0.95-0.84 (m, 6H).

Synthesis of 24.9

A solution of 24.8 (2.0 g, 6.05 mmol) in THF (30 mL) was added BH₃ Me₂S(2.42 mL, 24.2 mmol, 10 M) stirred at 25° C. for 16 hours. To theresulting mixture was added ethanol (6.05 mL, 60.5 mmol, 10 M) at 15°C., followed by NaOH aqueous (12.1 mL, 5.0 M, 60.5 mmol) at 0° C.Hydrogen peroxide (6.05 mL, 10 M, 60.5 mmol) was added dropwise at 0° C.The reaction mixture was stirred at 70° C. for 1 hour. The mixture wascooled to 15° C. and Na₂S₂O₃ (100 mL, sat. aq.) was added. The aqueouswas extracted with EtOAc (100 mL×3). The combined organic layer waswashed with brine (2×50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn (0˜50% of EtOAc in PE) to give 24.9 (1.8 g, 85.7%). ¹H NMR (400MHz, CDCl₃) δ_(H) 4.17-4.08 (m, 1H), 2.98 (s, 1H), 2.03-1.74 (m, 5H),1.72-1.32 (m, 14H), 1.31-1.23 (m, 8H), 1.20-1.11 (m, 3H), 1.09-0.92 (m,5H), 0.90-0.74 (m, 4H).

Synthesis of 24.10

To a solution of 24.9 (1.75 g, 5.02 mmol) in DCM (40 mL) was addedDess-martin reagent (4.24 g, 10.0 mmol) at 25° C. The reaction mixturewas stirred at 25° C. for 20 min. The mixture was quenched by saturatedNaHCO₃ aqueous (30 mL) at 10° C. The DCM phase was separated and washedwith saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3×50 mL), brine (2×20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column (0˜60% ethyl acetate in PE) to give24.10 (1.1 g, 63.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.51-2.44 (m, 1H),2.26 (dd, J=2.9, 12.7 Hz, 1H), 2.16-2.11 (m, 3H), 2.04-1.73 (m, 6H),1.70-1.46 (m, 9H), 1.44-1.29 (m, 7H), 1.26-1.22 (m, 3H), 1.20-1.02 (m,3H), 1.00 (d, J=4.5 Hz, 3H), 0.83 (dd, J=3.1, 7.4 Hz, 3H).

Synthesis of 24.11

To a solution of 24.10 (1.1 g, 3.17 mmol) in MeOH (10 mL) at 0° C. wasadded MeONa (3.42 g, 63.4 mmol) and the reaction was stirred at 80° C.for 16 hours. Then the residue was poured into saturated NH₄Cl (100 mL).The aqueous phase was extracted with EtOAc (2×100 mL). The combinedorganic phase was washed with saturated brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 24.11 (1.0 g,91.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.26 (dd, J=3.0, 12.8 Hz, 1H),2.15 (s, 3H), 2.04-1.97 (m, 1H), 1.90-1.82 (m, 2H), 1.81-1.75 (m, 2H),1.71-1.57 (m, 4H), 1.50-1.30 (m, 10H), 1.27 (s, 6H), 1.09-1.00 (m, 2H),0.99 (s, 3H), 0.97-0.92 (m, 1H), 0.83 (d, J=7.5 Hz, 3H). LC-ELSD/MSpurity: 99%, MS ESI calcd. for C₂₃H₃₈O₂ [M−H₂O+H]⁺ 329.2, found C₂₃H₃₈O₂[M−H₂O+H]⁺ 329.3.

Synthesis of 24.12

To a mixture of MePPh₃Br (7.36 g, 20.7 mmol) in THF (80 mL) was addedt-BuOK (2.32 g, 20.7 mmol) at 20° C. under N₂. The resulting mixture wasstirred at 60° C. for 30 min. Compound 24.11 (900 mg, 2.59 mmol) in THF(10 mL) was added in portions below 60° C. The reaction mixture wasstirred at 60° C. for 16 hours. The reaction mixture was quenched with10% NH₄Cl aqueous (200 mL) at 15° C. The organic layer was separated.The aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic phase was washed with brine (2×50 mL), filtered, concentratedunder reduced pressure. The residue was purified by flash column (0˜20%ethylacetate in PE) to give 24.12 (770 mg, 86.3%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 4.80 (s, 1H), 4.62 (d, J=2.0 Hz, 1H), 2.01-1.59 (m, 12H),1.55-1.46 (m, 3H), 1.43-1.28 (m, 7H), 1.26 (s, 5H), 1.22-1.15 (m, 1H),1.08-0.92 (m, 4H), 0.90 (s, 3H), 0.82 (d, J=7.5 Hz, 3H).

Synthesis of 24.13

To a mixture of 24.12 (300 mg, 0.8706 mmol) in DCM (5 ml) was addedm-CPBA (374 mg, 1.74 mmol, 80% purity). The mixture was stirred at 25°C. for 12 hours. Saturated aqueous NaHCO₃ (30 mL) and Na₂S₃O₃ (30 mL)was added and the mixture was stirred for another 5 mins. The aqueousphase was extracted with DCM (3×30 mL). The combined organic phase waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 24.13 (180 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.73(d, J=5.0 Hz, 1H), 2.65 (d, J=4.8 Hz, 1H), 2.05-1.82 (m, 3H), 1.80-1.72(m, 3H), 1.71-1.61 (m, 5H), 1.55-1.46 (m, 4H), 1.42-1.29 (m, 6H), 1.26(s, 4H), 1.25 (s, 3H), 1.23-1.03 (m, 4H), 1.00 (s, 3H), 0.97-0.88 (m,3H), 0.80 (d, J=7.3 Hz, 3H).

Synthesis of 24 and 25

To a solution of 24.13 (180 mg, 0.4991 mmol) in DMF (5 mL) was added1H-pyrazole-4-carbonitrile (138 mg, 1.49 mmol) and Cs₂CO₃ (488 mg, 1.49mmol) at 25° C. The mixture was stirred at 145° C. for 48 hours. Themixture was washed with water (5 mL) and extracted with EtOAc (50 mL×3).The combined organic layer was washed with brine (30 mL×2), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column (0%-70% of EtOAc in PE) to give 24 (49.6 mg,21.9%) and 25 (20 mg). Compound 25 (20 mg) was further purified by SFC(column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); Mobile phase: A:CO₂ B: 0.1% NH₃H₂O IPA; gradient: from 50% to 50% of B. Flow Rate(ml/min): 80) to give 25 (9.4 mg, 4.15%).

24: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.91 (s, 1H), 7.79 (s, 1H), 4.49-4.12(m, 2H), 2.41 (s, 2H), 2.07-2.00 (m, 1H), 1.91-1.84 (m, 1H), 1.81-1.73(m, 2H), 1.70-1.59 (m, 5H), 1.48-1.31 (m, 7H), 1.27 (s, 7H), 1.11 (s,3H), 1.07-1.03 (m, 1H), 1.01 (s, 5H), 0.81 (d, J=7.5 Hz, 3H). LC-ELSD/MSpurity: 99%, MS ESI calcd. for C₂₈H₄₃N₃O₂ [M−2H₂O+H]⁺ 418.3, foundC₂₈H₄₃N₃O₂ [M−2H₂O+H]⁺ 418.4.

25: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.87 (d, J=1.8 Hz, 2H), 4.30 (d,J=13.9 Hz, 1H), 4.01 (d, J=13.9 Hz, 1H), 3.11 (s, 1H), 2.44 (d, J=5.6Hz, 1H), 2.10-1.92 (m, 1H), 1.91-1.80 (m, 1H), 1.79-1.70 (m, 2H),1.68-1.57 (m, 3H), 1.52-1.28 (m, 9H), 1.25 (s, 6H), 1.20 (s, 3H),1.17-1.12 (m, 1H), 1.10 (s, 3H), 1.02-0.83 (m, 5H), 0.79 (d, J=7.5 Hz,3H), 0.70 (d, J=11.6 Hz, 1H). LC-ELSD/MS purity: 99%, MS ESI calcd. forC₂₈H₄₃N₃O₂ [M−2H₂O+H]⁺ 418.3, found C₂₈H₄₃N₃O₂ [M−2H₂O+H]⁺ 418.3.

Example 26 & 27:1-((S)-2-hydroxy-2-((1S,3S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-3,4,8,12a-tetramethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(26) &1-((R)-2-hydroxy-2-((1S,3S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-3,4,8,12a-tetramethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(27)

Synthesis of 26.1

To a solution of t-BuOK (4.64 g, 41.4 mmol) in THF (80 mL) was added24.7 (6.6 g, 20.7 mmol) at 25° C. under N₂. The mixture was stirred at25° C. for 10 min. Then methyl benzenesulfinate (6.46 g, 41.4 mmol) wasadded. The mixture was stirred at 30° C. for 0.5 h. The mixture wasquenched by H₂O (100 mL) and extracted with EtOAc (3×80 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give 26.1 (9.16 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)7.81-7.60 (m, 2H), 7.57-7.41 (m, 3H), 4.28 (dd, J=13.9, 5.4 Hz, 1H),3.85 (dd, J=13.8, 5.8 Hz, 1H), 3.79-3.69 (m, 1H), 3.60-3.42 (m, 1H),2.45-2.13 (m, 1H), 1.96-1.58 (m, 6H), 1.54-1.30 (m, 6H), 1.28-1.23 (m,5H), 1.08 (s, 1H), 1.05-0.90 (m, 3H).

Synthesis of 26.2

To a mixture of 26.1 (9.16 g, 20.6 mmol) in xylene (100 mL) was addedNa₂CO₃ (32.7 g, 309 mmol) in portions. The reaction mixture was stirredat 140° C. for 12 hrs under N₂. The mixture was filtered andconcentrate. The residue was purified by silica gel chromatography(0-30% of EtOAc in PE) to give the 26.2 (5.2 g, 79.8%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 6.86 (dd, J=5.3, 10.0 Hz, 1H), 5.99-5.79 (m, 1H), 2.76-2.49(m, 1H), 2.02-1.57 (m, 8H), 1.45-1.30 (m, 8H), 1.28 (s, 4H), 1.13-1.09(m, 6H), 1.05-0.80 (m, 3H).

Synthesis of 26.3

To a solution of MeMgBr (8.39 mL, 25.2 mmol, 3M) in THF (20 mL) wasadded CuI (3.59 g, 18.9 mmol) at 0° C. and stirred at 0° C. for 1 hour,then 26.2 (2.0 g, 6.31 mmol) in THE (20 mL) was added at 0° C. Afterstirring at 0° C. for 3 hours, the mixture was poured into saturatedNH₄Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organiclayer was washed with brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0%˜30% of EtOAc in PE) to give 26.3 (1.92 g, 91.8%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.76 (dd, J=5.0, 14.3 Hz, 1H), 2.11-2.04 (m, 1H), 2.00-1.85(m, 3H), 1.84-1.56 (m, 9H), 1.44-1.30 (m, 9H), 1.27 (s, 4H), 1.17-1.09(m, 5H), 1.06 (d, J=7.3 Hz, 3H), 0.99 (d, J=7.0 Hz, 3H).

Synthesis of 26.4

To a mixture of EtPPh₃Br (16.0 g, 43.2 mmol) in THF (70 mL) was addedt-BuOK (4.84 g, 43.2 mmol) at 20° C. under N₂. The resulting mixture wasstirred at 50° C. for 30 min. Compound 26.3 (1.8 g, 5.17 mmol) in THF(20 mL) was added in portions below 50° C. The reaction mixture wasstirred at 80° C. for 16 hours. The reaction mixture was quenched with10% NH₄Cl aqueous (200 mL) at 15° C. The organic layer was separated.The aqueous layer was extracted with EtOAc (3×150 mL). The combinedorganic phase was washed with brine (2×100 mL), filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn (0%˜20% of EtOAc in PE) to give 26.4 (1.5 g, 80.6%). ¹H NMR (400MHz, CDCl₃) δ_(H) 5.39-5.16 (m, 1H), 2.42-2.26 (m, 1H), 2.24-2.15 (m,1H), 1.96-1.87 (m, 1H), 1.82-1.57 (m, 10H), 1.56 (s, 5H), 1.54-1.47 (m,2H), 1.43-1.29 (m, 7H), 1.27 (s, 5H), 1.25-1.17 (m, 3H), 1.06-1.02 (m,1H), 1.00 (s, 3H), 0.94 (d, J=7.3 Hz, 3H), 0.88 (d, J=7.0 Hz, 3H).

Synthesis of 26.5

A solution of 26.4 (500 mg, 4.35 mmol) in THF (30 mL) was added BH₃ Me₂S(1.73 mL, 17.4 mmol 10 M) stirred at 25° C. for 16 hours. To theresulting mixture was added ethanol (4.34 mL, 43.4 mmol, 10 M) at 15°C., followed by NaOH aqueous (8.68 mL, 5.0 M, 43.4 mmol) at 0° C.Hydrogen peroxide (4.34 mL 10 M, 43.4 mmol) was added dropwise at 0° C.The reaction mixture was stirred at 80° C. for 1 hour. The mixture wascooled to 15° C. and Na₂S₂O₃ (150 mL, sat. aq.) was added. The aqueouslayer was extracted with EtOAc (100 mL×3). The combined organic layerwas washed brine (2×50 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash column (0˜30%of EtOAc in PE) to give 26.5 (1.3 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.98(t, J=6.0 Hz, 1H), 1.91-1.78 (m, 3H), 1.71-1.55 (m, 8H), 1.51-1.36 (m,13H), 1.27 (d, J=3.3 Hz, 11H), 1.20 (d, J=6.3 Hz, 5H), 1.11 (s, 3H),0.94 (d, J=6.5 Hz, 3H), 0.89 (d, J=7.3 Hz, 5H), 0.87-0.78 (m, 5H).

Synthesis of 26.6

To a solution of 26.5 (1 g, 2.75 mmol) in DCM (10 mL) was addedDess-martin reagent (2.33 g, 5.50 mmol) at 25° C. The reaction mixturewas stirred at 25° C. for 20 min. The mixture was quenched withsaturated NaHCO₃ aqueous (50 mL) at 10° C. The DCM phase was separatedand washed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3×50 mL), brine(2×20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash column (0˜30% ethyl acetatein PE) to give 26.6 (740 mg, 74.6%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.54(dd, J=6.3, 10.0 Hz, 1H), 2.14 (s, 3H), 1.88-1.77 (m, 3H), 1.68-1.52 (m,10H), 1.49-1.26 (m, 12H), 1.25 (s, 3H), 1.24-1.18 (m, 2H), 1.14 (s, 3H),1.09-0.99 (m, 3H), 0.96 (d, J=6.8 Hz, 4H), 0.91-0.87 (m, 3H).

Synthesis of 26.7

To a solution of 26.6 (640 mg, 1.77 mmol) in MeOH (20 mL) at 0° C. wasadded MeONa (1.91 g, 35.4 mmol). After stirring at 80° C. for 16 hours,the mixture was poured into saturated NH₄Cl (100 mL). The aqueous phasewas extracted with EtOAc (2×100 mL). The combined organic phase waswashed with saturated brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0˜25% ethyl acetate in PE) to give 26.7 (300 mg, 47.0%). ¹H NMR (400MHz, CDCl₃) δ_(H) 2.52 (d, J=10.5 Hz, 1H), 2.14 (s, 3H), 2.12-2.04 (m,1H), 1.95-1.73 (m, 5H), 1.69-1.59 (m, 3H), 1.53-1.31 (m, 9H), 1.27 (s,5H), 1.23-1.14 (m, 3H), 1.03 (d, J=7.3 Hz, 3H), 0.97 (s, 4H), 0.86 (d,J=7.5 Hz, 3H).

Synthesis of 26.8

To a mixture of MePPh₃Br (2.36 g, 6.65 mmol) in THF (20 mL) was addedt-BuOK (746 mg, 6.65 mmol) at 20° C. under N₂. The resulting mixture wasstirred at 80° C. for 30 min. Compound 26.7 (300 mg, 0.8319 mmol) in THF(5 mL) was added in portions below 80° C. The reaction mixture wasstirred at 80° C. for 16 hours. The reaction mixture was quenched with10% NH₄Cl aqueous (50 mL) at 15° C. The organic layer was separated. Theaqueous layer was extracted with EtOAc (3×50 mL). The combined organicphase was washed with brine (2×30 mL), filtered and concentrated underreduced pressure. The residue was purified by flash column (0˜20% EA inPE) to give 26.8 (130 mg, 43.6%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.81 (s,1H), 4.64 (s, 1H), 2.09-1.99 (m, 2H), 1.93-1.75 (m, 4H), 1.72 (s, 3H),1.68-1.59 (m, 3H), 1.55-1.31 (m, 9H), 1.26 (s, 6H), 1.22-1.16 (m, 2H),1.13-1.06 (m, 2H), 1.04 (d, J=7.3 Hz, 3H), 0.88 (s, 3H), 0.85 (d, J=7.5Hz, 3H).

Synthesis of 26.9

To a mixture of 26.8 (130 mg, 0.36 mmol) in DCM (5 ml) was added m-CPBA(156 mg, 0.725 mmol, 80% purity). The mixture was stirred at 25° C. for12 hours. Saturated aqueous NaHCO₃ (30 mL) and Na₂S₃O₃ (30 mL) wereadded and the mixture was stirred for another 5 mins. The aqueous phasewas extracted with DCM (3×30 mL). The combined organic phase was washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 26.9 (150 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.75(d, J=4.8 Hz, 1H), 2.65 (d, J=4.8 Hz, 1H), 2.04-1.94 (m, 1H), 1.92-1.77(m, 4H), 1.70-1.58 (m, 4H), 1.56-1.31 (m, 8H), 1.27 (s, 4H), 1.24 (s,3H), 1.21-1.07 (m, 4H), 1.03-1.00 (m, 2H), 0.99-0.94 (m, 6H), 0.84 (d,J=7.5 Hz, 3H).

Synthesis of 26 and 27

To a solution of 26.9 (150 mg, 0.4004 mmol) in DMF (5 mL) was added1H-pyrazole-4-carbonitrile (111 mg, 1.20 mmol) and Cs₂CO₃ (390 mg, 1.20mmol) at 25° C. The mixture was stirred at 145° C. for 16 hours. Themixture was washed with water (5 mL) and extracted with EtOAc (50 mL×3).The combined organic layer was washed with brine (30 mL×2), dried overNa₂SO₄, filtered, concentrated under reduced pressure. The residue waspurified by column (0%-70% of EtOAc in PE) to give a mixture of 26 & 27(180 mg). The was purified by SFC (column: DAICEL CHIRALCEL OJ-H (250mm*30 mm, 5 um); Mobile phase: A: CO₂ B: 0.1% NH₃H₂O ETOH; gradient:from 20% to 20% of B. Flow Rate (ml/min): 70) to give 26 (5.1 mg, 2.72%)and 27 (29.7 mg, 15.8%).

26: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.87 (s, 2H), 4.32-3.94 (m, 2H), 3.36(s, 1H), 2.46 (d, J=8.3 Hz, 1H), 1.95-1.57 (m, 8H), 1.52-1.27 (m, 10H),1.25 (s, 4H), 1.20 (s, 3H), 1.09 (s, 3H), 1.08-0.98 (m, 3H), 0.96-0.87(m, 3H), 0.83 (dd, J=5.1, 7.2 Hz, 5H). LC-ELSD/MS purity: 99%, MS ESIcalcd. for C₂₉H₄₅N₃O₂ [M−2H₂O+H]⁺ 432.3, found C₂₉H₄₅N₃O₂ [M−2H₂O+H]⁺432.4.

27: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.91 (s, 1H), 7.79 (s, 1H), 4.44-4.16(m, 2H), 2.44-2.36 (m, 2H), 1.93-1.57 (m, 10H), 1.54-1.29 (m, 10H), 1.27(s, 4H), 1.24-1.18 (m, 2H), 1.10 (s, 3H), 1.03 (d, J=7.3 Hz, 3H), 0.99(s, 4H), 0.84 (d, J=7.5 Hz, 3H). LC-ELSD/MS purity: 99%, MS ESI calcd.for C₂₉H₄₅N₃O₂ [M−2H₂O+H]⁺ 432.3, found C₂₉H₄₅N₃O₂ [M−2H₂O+H]⁺ 432.3.

Example 30:1-((R)-2-hydroxy-2-((1S,3aS,3bR,5aS,7S,8aS,8bS,10aS)-7-hydroxy-8a,10a-dimethyl-7-propylhexadecahydrodicyclopenta[a,f]naphthalen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(30)

Synthesis of 30.1

To a solution of pregnanolone (50 g, 157 mmol) in EtOH (250 mL) and THF(250 mL) was added Pd/C (5 g, <1% water). Then the solution washydrogenated under 30 psi of hydrogen at 25° C. for 16 hrs. The reactionwas worked up with another 3 batches from 50 g of pregnanolone. Themixture was filtered through a pad of celite and the filtrate wasconcentrated under reduced pressure to afford 30.1 (188 g, 94%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.70-3.50 (m, 1H), 2.60-2.45 (m, 1H), 2.25-1.90(m, 5H), 1.80-1.50 (m, 8H), 1.45-1.05 (m, 10H), 1.00-0.50 (m, 9H).

Synthesis of 30.2

Liquid bromine (45.0 g, 282 mmol) was added slowly to stirring NaOHaqueous (376 mL, 3 M, 1129 mmol) at 0° C. When all the bromine wasdissolved, the mixture was diluted with cold dioxane (90 mL) and addedslowly to a stirred solution of 30.1 (30 g, 94.1 mmol) in dioxane (210mL) and water (90 mL). After stirring at 25° C. for 5 h, the remainingoxidizing reagent was quenched with Na₂S₂O₃ (300 mL, aq.) and themixture was then heated to 80° C. until the solid material wasdissolved. The solution was acidified with HCl (3 M, 50 mL) and a solidwas precipitated. The solid was filtered and washed with water (3×100mL) to give a solid, which was dried under reduced pressure to afford30.2 (28 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.66-3.51 (m, 1H), 2.37 (t,J=9.2 Hz, 1H), 2.13-2.00 (m, 2H), 1.88-1.77 (m, 3H), 1.75-1.64 (m, 4H),1.60-1.57 (m, 1H), 1.47-1.32 (m, 3H), 1.32-1.20 (m, 6H), 1.16-1.04 (m,2H), 1.04-0.84 (m, 2H), 0.81 (s, 3H), 0.73-0.65 (m, 4H).

Synthesis of 30.3

A mixture of 30.2 (28 g, 87.3 mmol), N, O-dimethylhydroxylaminehydrochloride (16.9 g, 174 mmol), HATU (39.5 g, 104 mmol) and Et₃N (50.4mL, 349 mmol) in anhydrous DCM (350 mL) was stirred at 25° C. for 18 h.Then the mixture was treated with water (200 mL) and extracted with DCM(2×400 mL). The combined organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (PE/EtOAc=5/1) to afford 30.3 (24g, 76%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.65-3.52 (m, 4H), 3.18 (s, 3H),2.23-2.09 (m, 1H), 1.84-1.62 (m, 7H), 1.60-1.50 (m, 2H), 1.42-1.34 (m,2H), 1.33-1.22 (m, 6H), 1.19-1.03 (m, 2H), 1.00-0.84 (m, 3H), 0.79 (s,3H), 0.73-0.65 (m, 4H).

Synthesis of 30.4

Concentrated H₂SO₄ (35.1 mL) was diluted with H₂O (140 mL). CrO₃ (31.5g, 316 mmol) was added. The fresh prepared reagent was added to asolution of 30.3 (24 g, 66.0 mmol) in AcOH (300 mL). After stirring at70° C. for 3 h to give a green solution, the mixture was diluted withwater (300 mL) and extracted with DCM (3×300 mL). The combined organicphase was washed with brine (2×200 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give 30.4 (30 g), which was used directlyfor next step without further purification.

Synthesis of 30.5

To a solution of 30.4 (30 g) in Ac₂O (250 mL) was added NaOAc (23.9 g,292 mmol). After stirring at 130° C. for 16 h to give a solution, thereaction mixture was quenched with water (100 mL) and extracted withEtOAc (3×200 mL). The combined organic phase was washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash column (10%˜20% of EtOAc in PE) to give 30.5 (8g).

Synthesis of 30.6

To a solution of 30.5 (8 g, 23.0 mmol) in MeOH (100 mL) was added NaBH₄(2.61 g, 69.0 mmol) at 25° C. After stirring at 25° C. for 30 min, thereaction was quenched with water (100 mL) and extracted with DCM (2×100mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash column (15%˜20% of EtOAc in PE) to give 30.6 (5.9 g).¹H NMR (400 MHz, CDCl₃) δ_(H) 4.47-4.31 (m, 1H), 3.63 (s, 3H), 3.19 (s,3H), 2.80-2.76 (m, 1H), 2.24-2.06 (m, 2H), 1.85-1.64 (m, 5H), 1.60-1.43(m, 7H), 1.32-1.23 (m, 3H), 1.21-1.04 (m, 2H), 1.02-0.93 (m, 2H), 0.90(s, 3H), 0.74 (s, 3H).

Synthesis of 30.7

To a solution of 30.6 (5.9 g, 16.8 mmol) in THF (100 mL) was addedMeMgBr (16.7 mL, 50.4 mmol, 3M) at −78° C. under N₂. The reaction waswarmed to 25° C. and stirred at 25° C. for 1 h. Then the reaction wasquenched with water (100 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn (10%˜15% of EtOAc in PE) to give 30.7 (4.2 g, 82%). ¹H NMR (400MHz, CDCl₃) δ_(H) 4.46-4.35 (m, 1H), 2.53 (t, J=9.0 Hz, 1H), 2.26-2.02(m, 5H), 2.03-1.94 (m, 1H), 1.75-1.58 (m, 3H), 1.55-1.47 (m, 3H),1.46-1.37 (m, 5H), 1.36-1.27 (m, 1H), 1.27-1.09 (m, 4H), 0.91 (s, 3H),0.88-0.79 (m, 1H), 0.79-0.70 (m, 1H), 0.61 (s, 3H).

Synthesis of 30.8

To a solution of trimethylsulfonium iodide (141 mg, 1.84 mmol) in DMSO(2 mL) was added NaH (73.5 mg, 1.84 mmol, 60% in oil) in THF (1 mL) andstirred at 0° C. for 1.0 h under N₂. Subsequently a solution of 30.7(222.9 mg, 0.73 mmol) in DMSO (2 mL) was added at 0° C. After stirringat 25° C. for 16 hrs, the reaction was treated with water (5 mL) andextracted with EtOAc (2×5 mL). The combined organic phase was washedwith water (2×5 mL), brine (10 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to give 30.8 (900 mg).¹H NMR (400 MHz, CDCl₃) δ_(H) 4.40-4.39 (m, 1H), 3.68-3.49 (m, 1H), 3.25(s, 1H), 2.61 (s, 1H), 2.49 (s, 1H), 2.33 (s, 1H), 2.04 (s, 3H),1.75-1.65 (m, 4H), 1.52-1.45 (m, 4H), 1.37 (s, 10H), 0.79 (s, 7H)

Synthesis of 30.9

To a solution of 30.8 (900 mg, 2.82 mmol) in DMF (10 mL) was added4-cyanopyrazole (1.04 g, 11.2 mmol) and Cs₂CO₃ (2.75 g, 8.46 mmol).After stirring at 120° C. for 16 hrs under N₂, the reaction mixture wasdiluted with water (10 mL) and extracted with EtOAc (3×10 mL). Thecombined organic layer was concentrated to give 30.9 (200 mg), which waspurified by SFC (Column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um);Condition: 0.1% NH₃H₂O ETOH; Begin B: 35%; End B: 35%) to afford (100mg, 50.2%). The solid was triturated from MeCN (2 mL) at 25° C. to give30.9 (84 mg, 84.0%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.80(s, 1H), 4.45-4.35 (m, 1H), 4.18-4.12 (m, 1H), 4.04-3.98 (m, 1H), 2.26(s, 1H), 2.04 (s, 4H), 1.75-1.65 (m, 3H), 1.45-1.31 (m, 6H), 1.26-1.14(m, 4H), 1.11-0.97 (m, 5H), 0.89 (d, J=13.6 Hz, 8H), 0.74-0.66 (m, 1H).LC-ELSD/MS purity 99%, MS ESI calcd for C₂₅H₃₄N₃ [M−2H₂O+H]⁺ 376.3 found376.3, analytic SFC 100% de.

Synthesis of 30.10

To a solution of 30.9 (34 mg, 0.083 mmol) in DCM (1 mL) was addedDess-Martin reagent (70 mg, 0.16 mmol) at 20° C. After stirring at 20°C. for 15 mins, the mixture was poured into saturated NaHCO₃/Na₂S₂O₃aqueous (1:1, 20 mL). The aqueous phase was extracted with EtOAc (3×10mL). The combined organic phase was washed with brine (2×10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give product, whichwas purified by prep-HPLC (column: Phenomenex Gemini-NX 80 mm*40 mm*3um, condition: water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN, begin B: 51, endB: 81, gradient time: 8 min, 100% B Hold Time: 2.3 min, flow rate: 30mL/min) to give 30.10 (5.8 mg, 38.9%). ¹H NMR (400 MHz, CDCl₃) δ_(H)7.88 (s, 1H), 7.80 (s, 1H), 4.21-4.11 (m, 1H), 4.05-3.96 (m, 1H), 2.35(s, 1H), 2.22-1.82 (m, 7H), 1.81-1.62 (m, 5H), 1.52-1.40 (m, 4H),1.35-1.15 (m, 3H), 1.09 (s, 3H), 1.05-0.95 (m, 2H), 0.89 (s, 3H), 0.84(s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd for C₂₅H₃₄N₃O [M−H₂O+H]⁺392.4 found 392.4.

Synthesis of 30

To a solution of n-PrMgCl (0.73 ml, 1.46 mmol, 2 M in ether) in THF (1mL) was added a solution of 30.10 (100 mg, 0.24 mmol) in THF (1 mL)dropwise at −40° C. under N₂. After stirring for 2 hrs at −40° C., themixture was poured into NH₄Cl (1 mL) and extracted with EtOAc (2×5 mL).The combined organic phase was washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 30 (68 mg), whichwas purified by SFC (Column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um);Condition: 0.1% NH₃H₂O ETOH; Begin B: 25%; End B: 25%) to afford (6.6mg, 9.72%).

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.21-4.10 (m,1H), 4.06-3.96 (m, 1H), 2.28 (s, 1H), 2.10-1.97 (m, 1H), 1.95-1.80 (m,1H), 1.78-1.75 (m, 1H), 1.72-1.59 (m, 5H), 1.54-1.36 (m, 9H), 1.35-1.13(m, 8H), 1.09 (s, 3H), 0.95-0.91 (m, 6H), 0.87 (s, 3H), 0.75-0.65 (m,1H). LC-ELSD/MS purity 99%, MS ESI calcd for C₂₈H₄₀N₃ [M−2H₂O+H]⁺ 418.4found 418.4, analytic SFC 100% de.

Example 31 & 32:1-((S)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8-(methoxymethyl)-4,12a-dimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(31) &1-((R)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8-(methoxymethyl)-4,12a-dimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(32)

Synthesis of 31.2

A stirred solution of iodotrimethyl-4-sulfane (27.1 g, 133.0 mmol) andNaH (5.31 g, 133.0 mmol, 60%) in DMSO (300 mL) was cooled at 0° C. for 1h under N₂. The mixture was added to a solution of 31.1 (35 g, 127.0mmol) in DMSO (100 mL) at 25° C. for 16 hrs. The reaction was treatedwith water (300 mL) and extracted with EtOAc (2×200 mL). The combinedorganic phase was washed with water (2×200 mL), brine (200 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give 31.2 (40 g). Synthesis of 31.3

To a freshly prepared MeONa (693.0 mmol) in MeOH (400 mL) was added 31.2(20 g, 69.3 mmol) and the resulting mixture was stirred at 70° C. for 16hrs. The reaction was treated with water (200 mL). The aqueous phase wasextracted with EtOAc (2×200 mL). The combined organic phase was washedwith brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn (0˜30% of EtOAc in PE) to give 31.3 (10 g, 47.8%). H NMR (400MHz, CDCl₃) δ_(H) 3.41-3.36 (m, 5H), 2.61 (s, 1H), 1.97-1.73 (m, 5H),1.68-1.33 (m, 10H), 1.32-0.99 (m, 8H), 0.91-0.81 (m, 3H).

Synthesis of 31.4

To a solution of t-BuOK (13.2 g, 118 mmol) in THF (400 mL) was added31.3 (19 g, 59.2 mmol) at 15° C. under N₂. The mixture was stirred at15° C. for 10 min. Then methyl benzenesulfinate (14.9 mL, 118 mmol) wasadded. The mixture was stirred at 30° C. for 0.5 h. The mixture wasquenched with H₂O (500 mL) and extracted with EtOAc (2×300 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give 31.4 (27 g).

Synthesis of 31.5

To a mixture of 31.4 (27 g, 60.7 mmol) in xylene (300 mL) was addedNa₂CO₃ (98.2 g, 910 mol) in portions. After stirring at at 125° C. for12 hrs under N₂, the mixture was filtered and concentrated. The residuewas purified by silica gel chromatography (0˜30% of EtOAc in PE) to give31.6 (6.2 g, 32.1%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.52 (br d, J=5.8 Hz,1H), 6.02 (dd, J=3.1, 5.9 Hz, 1H), 3.47-3.29 (m, 5H), 2.61 (br s, 1H),2.37 (br d, J=10.0 Hz, 1H), 1.91-1.58 (m, 11H), 1.53-1.29 (m, 7H), 1.07(s, 3H).

Synthesis of 31.6

To a solution of MeMgBr (19.4 mL, 58.2 mmol, 3 M) in THF (40 mL) wasadded CuI (11.0 g, 58.2 mmol) at 0° C. After stirring at 0° C. for 1hour, 31.5 (6.2 g, 19.4 mmol) in THE (40 mL) was added at 0° C. Afterstirring at 0° C. for 3 hours, the mixture was poured into saturatedNH₄Cl (100 mL) and extracted with EtOAc (3×50 mL). The combined organiclayer was washed with brine (2×100 mL), dried over anhydrous Na₂SO₄,filtered, concentrated and purified by flash column (0%˜40% of EtOAc inPE) to give 31.6 (4.5 g, 69.4%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.46-3.34(m, 5H), 2.53-2.19 (m, 3H), 1.88-1.56 (m, 10H), 1.53-1.29 (m, 8H),1.24-1.17 (m, 2H), 1.10 (d, J=7.3 Hz, 3H), 1.03 (s, 3H).

Synthesis of 31.7

To a solution of 31.6 (4.5 g, 13.4 mmol) and ethyl diazoacetate (6.11 g,53.6 mmol) in THF (150 mL) was added a freshly prepared LDA (53.6 mL,1.0 M, 53.6 mmol) at −78° C. After stirring at −78° C. for 3 h, aceticacid (3.21 g, 53.6 mmol) in THF (50 mL) was added. Then the resultingreaction mixture was stirred at 15° C. for 16 h. The mixture was pouredinto water (150 mL). The aqueous phase was extracted with EtOAc (3×100mL). The combined organic layers were washed with brine (300 mL), driedover anhydrous Na₂SO₄, filtered and evaporated under reduced pressure togive 31.7 (9.0 g).

Synthesis of 31.8

To a solution of 31.7 (9.0 g) in DME (100 mL) was added Rh₂(OAc)₄ (220mg, 0.5 mmol) in one portion at 15° C. After stirring at 15° C. for 12hours, the mixture was concentrated to give 31.8 (9 g).

Synthesis of 31.9

To a solution of 31.8 (9 g) in MeOH (100 mL) was added KOH (11.9 g, 213mmol) at 15° C. After stirring at at 70° C. for 1 h, the reactionmixture was poured into H₂O (50 mL), and the aqueous layer was extractedwith EtOAc (3×30 mL). The combined organic layer was washed with brine(100 mL), dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by flash column (0˜15% of EtOAc in PE) to give 31.9 (2.3 g,30.9%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.47-3.30 (m, 5H), 2.79 (ddd,J=7.7, 12.1, 14.4 Hz, 1H), 2.22-2.10 (m, 2H), 1.93-1.47 (m, 13H),1.46-1.28 (m, 7H), 1.16 (s, 3H), 1.06 (d, J=7.5 Hz, 3H), 0.99-0.74 (m,2H).

Synthesis of 31.10

To a suspension of Ph₃PEtBr (12.2 g, 32.9 mmol) in anhydrous THF (80 mL)was added t-BuOK (3.69 g, 32.9 mmol) at 15° C. under N₂ and thesuspension was stirred at 60° C. for 30 min. Then a solution of 31.9(2.3 g, 6.59 mmol) in anhydrous THF (50 mL) was dropwise. After stirringat 60° C. for 16 h, the mixture was cooled and poured into ice-water(100 mL) and stirred for 10 min. The aqueous phase was extracted withEtOAc (2×100 mL). The combine organic phase was washed with brine (2×200mL), filtered, concentrated and purified by flash column (0˜10% of EtOAcin PE) to give 31.10 (1.9 g, 80.1%). ¹H NMR (400 MHz, CDCl₃) δ_(H)5.26-5.03 (m, 1H), 3.45-3.30 (m, 5H), 2.55 (br s, 1H), 2.40 (td, J=3.4,14.0 Hz, 1H), 2.29-2.18 (m, 1H), 2.15-2.01 (m, 2H), 1.89 (br d, J=13.8Hz, 1H), 1.80-1.58 (m, 9H), 1.50-1.13 (m, 11H), 1.09-1.03 (m, 1H), 1.00(s, 3H), 0.90 (dd, J=7.4, 15.7 Hz, 4H).

Synthesis of 31.11

To a solution of 31.10 (1.8 g, 4.99 mmol) in THF (50 mL) was addedBH₃.Me₂S (14.9 mL, 14.9 mmol, 1 M in THF) at 25° C. After stirring at50° C. for 16 hours, the reaction mixture was cooled and quenched withEtOH (3.18 mL, 2.29 g, 49.9 mmol) at 0° C., followed by adding NaOH(9.97 mL, 5M, 49.9 mmol) very slowly. After the addition, H₂O₂ (4.98 mL,49.9 mmol, 10 M in water) was added slowly until the inner temperatureno longer rised and the inner temperature was maintained below 30° C.The mixture was stirred at 50° C. for another 1 h. The aqueous phase wasextracted with ethyl acetate (3×50 mL). The combined organic phase waswashed with saturated Na₂S₂O₃ (2×100 mL), brine (2×100 mL), drive overanhydrous Na₂SO₄, filtered and concentrated to give 31.11 (1.8 g).

Synthesis of 31.12

To a solution of 31.11 (1.8 g, 4.93 mmol) in DCM (50 mL) was addedDess-Martin reagent (4.18 g, 9.86 mmol). After stirring at 25° C. for 30mins, the mixture was quenched by saturated NaHCO₃ aqueous (30 mL). TheDCM phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous(1:1, 2×30 mL), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 31.12 (1.8 g).

Synthesis of 31.12a

To a solution of 31.12 (1.9 g, 5.04 mmol) in MeOH (100 mL) at 0° C. wasadded MeONa (4.08 g, 75.6 mmol). After stirring at 70° C. for 16 h, theresidue was poured into saturated NH₄Cl (100 mL). The aqueous phase wasextracted with EtOAc (2×100 mL). The combined organic phase was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 31.12a (2.1 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)3.45-3.34 (m, 5H), 2.60 (br s, 1H), 2.28 (dd, J=2.9, 12.6 Hz, 1H), 2.16(s, 3H), 2.05-1.61 (m, 9H), 1.48-1.14 (m, 12H), 1.08-0.94 (m, 6H), 0.84(d, J=7.5 Hz, 3H).

Synthesis of 31.13

To a suspension of MePh₃PBr (3.28 g, 9.29 mmol) in anhydrous THF (20 mL)was added t-BuOK (1.04 g, 9.29 mmol) at 15° C. under N₂. Ater stirringat 60° C. for 30 min, then a solution of 31.12a (350 mg, 0.93 mmol) inanhydrous THF (10 mL) was added dropwise. After stirring at 60° C. for16 h, the mixture was cooled and poured into ice-water (50 mL) andstirred for 10 min. The aqueous phase was extracted with EtOAc (2×50mL). The combined organic phase was washed with brine (100 mL),filtered, concentrated and purified by flash column (0˜10% of EtOAc inPE) to give 31.13 (280 mg, 80.4%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.80(s, 1H), 4.62 (d, J=2.0 Hz, 1H), 3.47-3.23 (m, 5H), 2.55 (br s, 1H),2.01 (br d, J=5.0 Hz, 1H), 1.90-1.57 (m, 11H), 1.49-1.14 (m, 10H),1.11-0.91 (m, 4H), 0.89 (s, 3H), 0.88-0.84 (m, 2H), 0.82 (d, J=7.5 Hz,3H).

Synthesis of 31.14

To a solution 31.13 (280 mg, 0.747 mmol) in DCM (5 mL) was added NaHCO₃(125 mg, 1.49 mmol). Then m-CPBA (301 mg, 1.49 mmol) was added to themixture at 0° C. under N₂. After stirring at 25° C. for 0.5 h, themixture was quenched with saturated NaHCO₃ (20 mL), the mixture wasextracted with DCM (2×20 mL). The combined organic layer was washed withNa₂S₂O₃ (2×20 mL, sat.), brine (2×40 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give 31.14 (200 mg).¹H NMR (400 MHz, CDCl₃) δ_(H) 3.40 (s, 5H), 2.74 (d, J=4.8 Hz, 1H), 2.65(d, J=4.8 Hz, 1H), 2.11-1.81 (m, 2H), 1.80-1.47 (m, 13H), 1.44-1.34 (m,4H), 1.26 (s, 6H), 1.00 (s, 3H), 0.98-0.91 (m, 2H), 0.81 (d, J=7.5 Hz,3H).

Synthesis of 31 & 32

To a solution of 31.14 (200 mg, 0.512 mmol) in DMF (3 mL) was added1H-pyrazole-4-carbonitrile (94.8 mg, 1.02 mmol) and Cs₂CO₃ (498 mg, 1.53mmol) at 20° C. After stirring at 130° C. for 72 hours, to the mixturewas added water (20 mL) and the mixture was extracted with EtOAc (2×30mL). The organic layer was separated, concentrated and purified by flashcolumn (0˜30% EtOAc in PE) to give 31 & 32 (140 mg). The twodiastereomers were purified by SFC (Column: DAICEL CHIRALCEL OD-H (250mm*30 mm, 5 um), Condition: 0.1% NH₃H₂O ETOH Begin B 35% End B 35%,Gradient Time (min) 100% B, Hold Time (min), Flow Rate (ml/min) 60,Injections 60) to afford 31 (Peak 1, Rt=3.513 min, 8.1 mg) and 32 (Peak2, Rt=3.933 min, 56.9 mg). Compound 31 was further purified by SFC(Column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um), Condition: 0.1%NH₃H₂O ETOH Begin B 35% End B 35%, Gradient Time (min) 100% B, Hold Time(min), Flow Rate (ml/min) 60, Injections 60) to afford 31 (Peak 1,Rt=1.598 min, 4.2 mg).

31 ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (d, J=1.5 Hz, 2H), 4.30 (d, J=13.8Hz, 1H), 4.03 (d, J=13.8 Hz, 1H), 3.43-3.35 (m, 5H), 2.53-2.39 (m, 1H),2.05-1.92 (m, 1H), 1.88-1.80 (m, 1H), 1.77-1.65 (m, 3H), 1.64-1.47 (m,3H), 1.46-1.24 (m, 9H), 1.20 (s, 5H), 1.11 (s, 3H), 1.06-0.85 (m, 6H),0.80 (d, J=7.5 Hz, 3H), 0.76-0.71 (m, 1H). LC-ELSD/MS purity 99%, MS ESIcalcd. For C₂₈H₃₈N₃ [M−2H₂O−MeOH+H]⁺ 416.3 found 416.3. SFC 99% de.

32 ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.80 (s, 1H), 4.45-4.35(m, 1H), 4.30-4.21 (m, 1H), 3.41 (s, 5H), 2.59 (s, 1H), 2.37 (s, 2H),2.11-1.97 (m, 1H), 1.90-1.82 (m, 1H), 1.78-1.62 (m, 5H), 1.57-1.54 (m,7H), 1.48-1.32 (m, 6H), 1.31-1.15 (m, 4H), 1.11 (s, 3H), 1.02 (s, 3H),0.82 (d, J=7.4 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. ForC₂₈H₃₈N₃ [M−2H₂O—CH₃OH+H]⁺ 416.3 found 416.3. SFC 99% de.

Example 33 & 34:1-((S)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(33) &1-((R)-2-hydroxy-2-((1S,4R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-4,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile(34)

Synthesis of 33.1

To a solution of t-BuOK (14.6 g, 131 mmol) in THF (250 mL) was added 8.2(21 g, 65.9 mmol) at 25° C. under N₂. After stirring at 25° C. for 10min, methyl benzenesulfinate (20.4 g, 131 mmol) was added. The mixturewas stirred at 30° C. for 0.5 h. The mixture was quenched by H₂O (200mL) and extracted with EtOAc (3×200 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give 33.1 (40 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.70-7.56(m, 5H), 3.57-3.55 (m, 1H), 2.47-2.43 (m, 1H), 2.35-1.66 (m, 8H),1.62-1.29 (m, 12H), 1.28-0.93 (m, 11H).

Synthesis of 33.2

To a mixture of 33.1 (40 g, 90.3 mmol) in xylene (200 mL) was addedNa₂CO₃ (143 g, 1.35 mmol) in portions. After stirring at 130° C. for 12hrs under N₂, the mixture was filtered and concentrated, the residue waspurified by silica gel chromatography (0-15% of EtOAc in PE) to give theproduct 33.2 (7.8 g, 27%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.53-7.51 (dd,J=6 Hz, 1H), 6.03-6.01 (m, 1H), 2.38-2.35 (m, 1H), 1.88-1.50 (m, 10H),1.49-1.20 (m, 13H), 1.07 (s, 3H), 0.94 (t, J=7.6 Hz, 3H).

Synthesis of 33.3

To a solution of MeMgBr (24.6 mL, 73.8 mmol, 3 M) in THF (100 mL) wasadded CuI (14.0 g, 73.8 mmol) at 0° C. After stirring at 0° C. for 1hour, then 33.2 (7.8 g, 24.6 mmol) in THF (100 mL) was added at 0° C.After stirring at 0° C. for 3 hours, the mixture was poured intosaturated NH₄Cl (100 mL) and extracted with EtOAc (2×500 mL). Thecombined organic layer was washed with brine (2×200 mL), dried overanhydrous Na₂SO₄, filtered, concentrated and purified by flash column(0˜20% of EtOAc in PE) to give 33.3 (6.5 g, 79.4%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.50-2.21 (m, 3H), 1.87-1.44 (m, 13H), 1.43-1.14 (m, 11H),1.10-1.08 (m, 3H), 1.03 (s, 3H), 0.94 (t, J=7.2 Hz, 3H).

Synthesis of 33.4

To a solution of 33.3 (6.5 g, 19.5 mmol) and ethyl diazoacetate (11.1 g,97.5 mmol) in THF (600 mL) was added a freshly prepared LDA (48.7 mL, 2M, 97.5 mmol) at −78° C. After stirring at −78° C. for 2 hrs, thenacetic acid (5.85 g, 97.5 mmol) in THF (20 mL) was added. After stirringat 15° C. for 16 hrs, the mixture was poured into water (1000 mL). Theaqueous phase was extracted with EtOAc (3×500 mL). The combined organiclayers were washed with brine (1500 mL), dried over anhydrous Na₂SO₄,filtered and evaporated under reduced pressure to give 33.4 (13 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 4.27-4.22 (m, 2H), 2.27-2.20 (m, 1H),1.99-1.52 (m, 7H), 1.48-1.33 (m, 9H), 1.32-1.06 (m, 14H), 1.03-0.97 (m,6H), 0.93 (t, J=7.2 Hz, 3H).

Synthesis of 33.5

To a solution of 33.4 (13 g) in DME (300 mL) was added Rh₂(OAc)₄ (385mg, 0.873 mmol) in one portion at 15° C. After stirring at 15° C. for 12hours, the mixture was concentrated to give 33.5 (12.5 g). ¹H NMR (400MHz, CDCl₃) δ_(H) 4.48-4.11 (m, 2H), 2.31-1.56 (m, 5H), 1.50-1.33 (m,7H), 1.31-1.17 (m, 15H), 1.16-1.01 (m, 8H), 0.88-0.85 (m, 3H), 0.78-0.76(m, 2H).

Synthesis of 33.6

To a mixture of 33.5 (12.5 g, 29.8 mmol) in MeOH (150 mL) was added KOH(9.98 g, 178 mmol). After stirring at 70° C. for 2 hrs to give amixture, the reaction mixture was concentrated. Then H₂O (300 mL) wasadded. The mixture was extracted with EtOAc (3×200 mL). The combinedorganic phase was washed with brine (2×200 mL), dried over anhydrousNa₂SO₄, filtered, concentrated and purified by flash column (0-20% ofEtOAc in PE) to give 33.6 (4.5 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)2.84-2.75 (m, 1H), 2.18-2.12 (m, 2H), 1.88-1.52 (m, 11H), 1.49-1.21 (m,13H), 1.16 (s, 3H), 1.10-0.97 (m, 5H), 0.93 (t, J=7.2 Hz; 3H).

Synthesis of 33.7

To a suspension of EtPPh₃Br (10.6 g, 28.8 mmol) in anhydrous THF (150mL) was added t-BuOK (3.23 g, 28.8 mmol) at 15° C. under N₂. Afterstirring at 60° C. for 30 mins, a solution of 33.6 (2 g, 5.77 mmol) inanhydrous THF (50 mL) was added. The reaction mixture was stirred for 16hrs. The mixture was cooled and poured into ice-water (200 mL). Theaqueous phase was extracted with EtOAc (2×100 mL). The combine organicphase was washed with brine (2×100 mL), filtered, concentrated andpurified by flash column (0-10% of EtOAc in PE) to give 33.7 (1.3 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 5.18-5.13 (m, 1H), 2.42-2.38 (m, 1H),2.27-2.00 (m, 2H), 1.88-1.58 (m, 7H), 1.56-1.41 (m, 6H), 1.40-1.16 (m,13H), 1.09-0.83 (m, 12H).

Synthesis of 33.8

To a solution of 33.7 (1.3 g, 3.62 mmol) in THF (30 mL) was addedBH₃.Me₂S (2.17 mL, 21.7 mmol, 10 M). After stirring at 25° C. for 16hours, the mixture was added ethanol (4.22 mL, 72.4 mmol) at 15° C.,followed by NaOH aqueous (14.4 mL, 5.0 M, 72.4 mmol) at 0° C. Hydrogenperoxide (7.24 mL, 10 M, 72.4 mmol) was added dropwise at 0° C. Thereaction mixture was stirred at 70° C. for 1 hour. The mixture wascooled to 15° C. and Na₂S₂O₃ (100 mL, sat. aq.) was added. The aqueouswas extracted with EtOAc (3×100 mL). The combined organic layer waswashed with brine (2×50 mL), dried over Na₂SO₄, filtered, concentratedunder reduced pressure and purified by flash column (0-50% of EtOAc inPE) to give 33.8 (1.4 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.14-4.05 (m,1H), 2.04-1.41 (m, 15H), 1.40-1.08 (m, 15H), 1.05-0.77 (m, 13H).

Synthesis of 33.9

To a solution of 33.8 (1.2 g, 3.18 mmol) in DCM (20 mL) was added DMP(2.69 g, 6.36 mmol) at 25° C. After stirring at 25° C. for 30 mins, themixture was quenched by saturated NaHCO₃ aqueous (30 mL) and extractedwith DCM (3×100 mL). The combined organic layer was washed with NaS₂O₃(3×100 mL) and concentrated. The residue was purified by flash column(0˜15% of EtOAc in PE) to give 33.9a (800 mg). To a solution of 33.9a(800 mg, 2.13 mmol) in MeOH (20 mL) at 0° C. was added MeONa (1.72 g,31.9 mmol). After stirring at 70° C. for 16 hrs, then the mixture wasadded saturated NH₄Cl (100 mL). The aqueous phase was extracted withEtOAc (2×200 mL). The combined organic phase was washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified byflash column (0˜15% of EtOAc in PE) to give 33.9 (600 mg). ¹H NMR (400MHz, CDCl₃) δ_(H) 2.28-2.24 (m, 1H), 2.14-2.11 (m, 3H), 2.02-1.97 (m,1H), 1.96-1.58 (m, 7H), 1.50-1.28 (m, 9H), 1.27-1.00 (m, 8H), 0.99 (s,3H), 0.95-0.82 (m, 10H).

Synthesis of 33.10

To a mixture of MePPh₃Br (4.71 g, 13.2 mmol) in THF (50 mL) was addedt-BuOK (1.48 g, 13.2 mmol) at 20° C. under N₂. After stirring at 60° C.for 30 min, 33.9 (500 mg, 1.33 mmol) in THF (10 mL) was added inportions below 60° C. The reaction mixture was stirred at 60° C. for 16hours. The reaction mixture was quenched with 10% NH₄Cl aqueous (100 mL)at 15° C. and extracted with EtOAc (3×50 mL). The combined organic phasewas washed with brine (100 mL), filtered, concentrated under reducedpressure and purified by flash column (0˜5% ethyl acetate in PE) to give33.10 (380 mg, 76.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.79 (s, 1H), 4.62(s, 1H), 2.04-1.96 (m, 1H), 1.85-1.70 (m, 6H), 1.668-1.47 (m, 7H),1.46-1.13 (m, 12H), 1.09-0.89 (m, 11H), 0.88-0.81 (m, 5H).

Synthesis of 33.11

To a solution 33.10 (190 mg, 0.509 mmol) in DCM (10 mL) was added NaHCO₃(84.8 mg, 1.01 mmol) and then m-CPBA (203 mg, 1.01 mmol) at 0° C. underN₂. After stirring at 25° C. for 0.5 h, the mixture was quenched withsaturated NaHCO₃ (20 mL) and extracted with DCM (2×20 mL). The organiclayer was washed with Na₂S₂O₃ (2×20 mL), brine (2×40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive 33.11 (400 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.74-2.64 (m, 2H),2.04-1.41 (m, 10H), 1.40-1.27 (m, 10H), 1.24 (s, 3H), 1.21-1.02 (m, 4H),0.99 (s, 3H), 0.96-0.91 (m, 7H), 0.84-0.75 (m, 5H).

Synthesis of 33 & 34

To a solution of 33.11 (400 mg, 1.02 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (284 mg, 3.06 mmol) and Cs₂CO₃ (997 mg, 3.06mmol). After stirring at 145° C. for 72 hrs, the mixture was quenchedwith water (5 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layer was washed with brine (30 mL×2), dried over Na₂SO₄,filtered, concentrated under reduced pressure and purified by column(0˜20% of EtOAc in PE) to give 33 & 34 (500 mg), which was purified bySFC twice (Column DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); Condition0.1% NH₃H₂O ETOH; Begin B 40%; End B 40%) to give 33 (Peak 1, 17.7 mg,Rt=3.654 min, 3.5%) and 34 (Peak 2, 82.9 mg, Rt=4.288 min, 16.5%).

33: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.86 (d, J=2 Hz, 2H), 4.31-4.27 (m,1H), 4.02-3.99 (m, 1H), 3.10 (s, 1H), 2.45-2.43 (m, 1H), 2.00-1.92 (m,1H), 1.82-1.44 (m, 10H), 1.39-1.13 (m, 15H), 1.10 (s, 3H), 1.00-0.82 (m,8H), 0.79-0.69 (m, 4H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₃₀H₄₄N₃ [M−2H₂O+H]⁺ 446.4, found 446.4. analytic SFC 100% de.

34: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (s, 1H), 7.79 (s, 1H), 4.40-4.37(m, 1H), 4.27-4.23 (m, 1H), 2.41-2.38 (m, 2H), 2.06-2.01 (m, 1H),1.85-1.59 (m, 7H), 1.58-1.45 (m, 8H), 1.41-1.16 (m, 12H), 1.10 (s, 3H),1.07-1.03 (m, 1H), 1.01s (s, 3H), 0.93 (t, J=7.2 Hz, 3H), 0.82-0.80 (m,3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₃₀H₄₄N₃ [M−2H₂O+H]⁺446.4, found 446.4. analytic SFC 98% de.

Steroid Inhibition of TBPS Binding

[³⁵S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using ratbrain cortical membranes in the presence of 5 mM GABA has been described(Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson etal, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol.Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaCl/50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 mL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 mLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 mM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 mM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [³⁵S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above.

In Table 2 below, A indicates a TBPS IC₅₀ (μM)<0.1 μM, B indicates aTBPS IC₅₀ (μM) of 0.1 μM to <1.0 μM, C indicates a TBPS IC₅₀ (μM) of≥1.0 μM.

TABLE 2 Example No. STRUCTURE IC₅₀ (μM)  1

B  2

B  6

B  7

B  8

B  9

A 10

B 11

B 12

A 13

B 14

A 15

B 16

B 17

C 18

B 19

A 20

A 21

B 22

C 23

B 24

A 25

A 26

A 27

A 30

C 31

A 32

A 33

A 34

A

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1-30. (canceled)
 31. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is selected from the group consisting ofsubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl; R⁵ is hydrogen or methyl; each instance of R²² isindependently selected from the group consisting of halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA),—OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R³)₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; n is 0, 1, 2, or 3; and t is 2 or
 3. 32. The compound orpharmaceutically acceptable salt of claim 31, wherein t is
 2. 33. Thecompound or pharmaceutically acceptable salt of claim 32, wherein R³ issubstituted or unsubstituted C₁₋₆ alkyl.
 34. The compound orpharmaceutically acceptable salt of claim 33, wherein R³ is C₁₋₃ alkyloptionally substituted with C₁₋₃ alkoxy.
 35. The compound orpharmaceutically acceptable salt of claim 34, wherein R³ is methyl,ethyl, propyl, n-propyl, butyl, —CH₂OCH₃, or —CH₂OCH₂CH₃.
 36. Thecompound or pharmaceutically acceptable salt of claim 32, wherein R¹⁹ ishydrogen or unsubstituted C₁₋₃ alkyl.
 37. The compound orpharmaceutically acceptable salt of claim 32, wherein each of R^(15a)and R^(15b) is independently hydrogen or substituted or unsubstitutedalkyl.
 38. The compound or pharmaceutically acceptable salt of claim 37,wherein each of R^(15a) and R^(15b) is independently hydrogen or methyl.39. The compound or pharmaceutically acceptable salt of claim 32,wherein each of R^(16a) and R^(16b) is hydrogen.
 40. The compound orpharmaceutically acceptable salt of claim 32, wherein

is a single bond, and R⁵ is hydrogen or methyl.
 41. The compound orpharmaceutically acceptable salt of claim 32, wherein

is a double bond, and R⁵ and one of R^(6a) and R^(6b) is absent.
 42. Thecompound or pharmaceutically acceptable salt of claim 32, wherein R^(X)is —OH, and R^(Y) is unsubstituted C₁₋₃ alkyl.
 43. The compound orpharmaceutically acceptable salt of claim 32, wherein n is 1 and R²² ishalogen, —CN, —OR^(GA), —N(R^(GA))₂, substituted or unsubstituted C₁₋₆alkyl, or substituted or unsubstituted C₃₋₆ carbocylyl, wherein eachinstance of R^(GA) is independently hydrogen or substituted orunsubstituted C₁₋₃ alkyl.
 44. The compound or pharmaceuticallyacceptable salt of claim 32, wherein each of R^(1a), R^(1b), R^(2a),R^(2b), R^(4a), R^(4b), R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), andR^(12b) is hydrogen.
 45. The compound or pharmaceutically acceptablesalt of claim 31, wherein the compound of Formula (I) is a compound ofFormula (I-a) or (I-b):

or a pharmaceutically acceptable salt thereof.
 46. The compound orpharmaceutically acceptable salt of claim 45, wherein the compound ofFormula (I-a) is a compound of Formula (I-c):

or a pharmaceutically acceptable salt thereof.
 47. The compound orpharmaceutically acceptable salt of claim 45, wherein the compound ofFormula (I-b) is a compound of Formula (I-d):

or a pharmaceutically acceptable salt thereof.
 48. A compound of Formula(II):

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; R¹⁸ is substituted or unsubstituted alkyl; and n is 0, 1, 2, or3; provided that when R⁵ is hydrogen, R¹⁸ is not —CH₃.
 49. The compoundor pharmaceutically acceptable salt of claim 48, wherein each of R^(1a),R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b), R^(11a),R^(11b), R^(12a), and R^(12b) is hydrogen.
 50. The compound orpharmaceutically acceptable salt of claim 49, wherein R^(X) is —OH, andR^(Y) is unsubstituted C₁₋₃ alkyl.
 51. The compound or pharmaceuticallyacceptable salt of claim 49, wherein n is 1 and R²² is halogen, —CN,—OR^(GA), —N(R^(GA))₂, substituted or unsubstituted C₁₋₆ alkyl, orsubstituted or unsubstituted C₃₋₆ carbocylyl, wherein each instance ofR^(GA) is independently hydrogen or substituted or unsubstituted C₁₋₃alkyl.
 52. The compound or pharmaceutically acceptable salt of claim 48,wherein the compound of Formula (II) is a compound of Formula (IIIa) or(IIIb)

or a pharmaceutically acceptable salt thereof.
 53. A compound of Formula(V):

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; and n is 0, 1, 2, or
 3. 54. A compound of Formula (VIa)

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; r is 2 or 3; and n is 0, 1, 2, or
 3. 55. The compound orpharmaceutically acceptable salt of claim 54, wherein R³ is substitutedor unsubstituted C₁₋₆ alkyl.
 56. The compound or pharmaceuticallyacceptable salt of claim 55, wherein R³ is C₁₋₃ alkyl optionallysubstituted with C₁₋₃ alkoxy.
 57. The compound or pharmaceuticallyacceptable salt of claim 56, wherein R³ is methyl, ethyl, propyl,n-propyl, butyl, —CH₂OCH₃, or —CH₂OCH₂CH₃.
 58. The compound orpharmaceutically acceptable salt of claim 54, wherein R¹⁹ is hydrogen orunsubstituted C₁₋₃ alkyl.
 59. The compound or pharmaceuticallyacceptable salt of claim 54, wherein each of R^(15a) and R^(15b) isindependently hydrogen or substituted or unsubstituted alkyl.
 60. Thecompound or pharmaceutically acceptable salt of claim 59, wherein eachof R^(15a) and R^(15b) is independently hydrogen or methyl.
 61. Thecompound or pharmaceutically acceptable salt of claim 54, wherein eachof R^(16a) and R^(16b) is hydrogen.
 62. The compound or pharmaceuticallyacceptable salt of claim 54, wherein

is a single bond, and R⁵ is hydrogen or methyl.
 63. The compound orpharmaceutically acceptable salt of claim 54, wherein

is a double bond, and R⁵ and one of R^(6a) and R^(6b) is absent.
 64. Thecompound or pharmaceutically acceptable salt of claim 54, wherein R^(X)is —OH, and R^(Y) is unsubstituted C₁₋₃ alkyl.
 65. The compound orpharmaceutically acceptable salt of claim 54, wherein n is 1 and R²² ishalogen, —CN, —OR^(GA), —N(R^(GA))₂, substituted or unsubstituted C₁₋₆alkyl, or substituted or unsubstituted C₃₋₆ carbocylyl, wherein eachinstance of R^(GA) is independently hydrogen or substituted orunsubstituted C₁₋₃ alkyl.
 66. The compound or pharmaceuticallyacceptable salt of claim 54, wherein the compound of Formula (VIa) is acompound of Formula (VIa-a):

or a pharmaceutically acceptable salt thereof.
 67. The compound orpharmaceutically acceptable salt of claim 66, wherein the compound ofFormula (VIa-a) is a compound of Formula (VIa-b):

or a pharmaceutically acceptable salt thereof.
 68. The compound orpharmaceutically acceptable salt of claim 66, wherein the compound ofFormula (VIa-b) is a compound of Formula (VIa-c) or (VIa-d):

or a pharmaceutically acceptable salt thereof.
 69. The compound orpharmaceutically acceptable salt of claim 54, wherein the compound ofFormula (VIa) is a compound of Formula (VIa-e):

or a pharmaceutically acceptable salt thereof.
 70. A compound of Formula(VIb)

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R_(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; p is 2 or 3; and n is 0, 1, 2, or
 3. 71. The compound orpharmaceutically acceptable salt of claim 70, wherein R³ is substitutedor unsubstituted C₁₋₆ alkyl.
 72. The compound or pharmaceuticallyacceptable salt of claim 71, wherein R³ is C₁₋₃ alkyl optionallysubstituted with C₁₋₃ alkoxy.
 73. The compound or pharmaceuticallyacceptable salt of claim 72, wherein R³ is methyl, ethyl, propyl,n-propyl, butyl, —CH₂OCH₃, or —CH₂OCH₂CH₃.
 74. The compound orpharmaceutically acceptable salt of claim 70, wherein R¹⁹ is hydrogen orunsubstituted C₁₋₃ alkyl.
 75. The compound or pharmaceuticallyacceptable salt of claim 70, wherein each of R^(15a) and R^(15b) isindependently hydrogen or substituted or unsubstituted alkyl.
 76. Thecompound or pharmaceutically acceptable salt of claim 75, wherein eachof R^(15a) and R^(15b) is independently hydrogen or methyl.
 77. Thecompound or pharmaceutically acceptable salt of claim 70, wherein eachof R^(16a) and R^(16b) is hydrogen.
 78. The compound or pharmaceuticallyacceptable salt of claim 70, wherein

is a single bond, and R⁵ is hydrogen or methyl.
 79. The compound orpharmaceutically acceptable salt of claim 70, wherein

is a double bond, and R⁵ and one of R^(6a) and R^(6b) is absent.
 80. Thecompound or pharmaceutically acceptable salt of claim 70, wherein R^(X)is —OH, and R^(Y) is unsubstituted C₁₋₃ alkyl.
 81. The compound orpharmaceutically acceptable salt of claim 70, wherein n is 1 and R²² ishalogen, —CN, —OR^(GA), —N(R^(GA))₂, substituted or unsubstituted C₁₋₆alkyl, or substituted or unsubstituted C₃₋₆ carbocylyl, wherein eachinstance of R^(GA) is independently hydrogen or substituted orunsubstituted C₁₋₃ alkyl.
 82. The compound or pharmaceuticallyacceptable salt of claim 70, wherein the compound of Formula (VIb) is acompound of Formula (VIb-b):

or a pharmaceutically acceptable salt thereof.
 83. The compound orpharmaceutically acceptable salt of claim 83, wherein the compound ofFormula (VIb-b) is a compound of Formula (VIb-c) or (VIb-d):

or a pharmaceutically acceptable salt thereof.
 84. The compound orpharmaceutically acceptable salt of claim 70, wherein the compound ofFormula (VIb) is a compound of Formula (VIb-e):

or a pharmaceutically acceptable salt thereof.
 85. A compound of Formula(VII)

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently selected fromthe group consisting of hydrogen, halogen, cyano, —NO₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1),—OS(═O)₂R^(A1), OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂,—N(R^(A1))C(═O)R^(A1), —N(R^(A1))C(═NR^(A1))R^(A1),—N(R^(A1))C(═O)OR^(A1), —N(R^(A1))C(═O)N(R^(A1))₂,—N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))C(═NR^(A1))N(R^(A1))₂,—N(R^(A1))S(═O)₂OR^(A1), —N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1),—SC(═O)_(R) ^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1),—S(═O)₂OR^(A1), or —S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to6-membered heterocyclyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; and n is 0, 1, 2, or
 3. 86. The compound or pharmaceuticallyacceptable salt of claim 85, wherein R³ is substituted or unsubstitutedC₁₋₆ alkyl.
 87. The compound or pharmaceutically acceptable salt ofclaim 86, wherein R³ is C₁₋₃ alkyl optionally substituted with C₁₋₃alkoxy.
 88. The compound or pharmaceutically acceptable salt of claim87, wherein R³ is methyl, ethyl, propyl, n-propyl, butyl, —CH₂OCH₃, or—CH₂OCH₂CH₃.
 89. The compound or pharmaceutically acceptable salt ofclaim 85, wherein R¹⁹ is hydrogen or unsubstituted C₁₋₃ alkyl.
 90. Thecompound or pharmaceutically acceptable salt of claim 85, wherein eachof R^(15a) and R^(15b) is independently hydrogen or substituted orunsubstituted alkyl.
 91. The compound or pharmaceutically acceptablesalt of claim 90, wherein each of R^(15a) and R^(15b) is independentlyhydrogen or methyl.
 92. The compound or pharmaceutically acceptable saltof claim 85, wherein each of R^(16a) and R^(16b) is hydrogen.
 93. Thecompound or pharmaceutically acceptable salt of claim 85, wherein

is a single bond, and R⁵ is hydrogen or methyl.
 94. The compound orpharmaceutically acceptable salt of claim 85, wherein

is a double bond, and R⁵ and one of R^(6a) and R^(6b) is absent.
 95. Thecompound or pharmaceutically acceptable salt of claim 85, wherein R^(X)is —OH, and R^(Y) is unsubstituted C₁₋₃ alkyl.
 96. The compound orpharmaceutically acceptable salt of claim 85, wherein n is 1 and R²² ishalogen, —CN, —OR^(GA), —N(R^(GA))₂, substituted or unsubstituted C₁₋₆alkyl, or substituted or unsubstituted C₃₋₆ carbocylyl, wherein eachinstance of R^(GA) is independently hydrogen or substituted orunsubstituted C₁₋₃ alkyl.
 97. The compound or pharmaceuticallyacceptable salt of claim 85, wherein the compound of Formula (VII) is acompound of Formula (VII-b)

or a pharmaceutically acceptable salt thereof.
 98. The compound orpharmaceutically acceptable salt of claim 97, wherein the compound ofFormula (VII-b) is a compound of Formula (VII-c):

or a pharmaceutically acceptable salt thereof.
 99. A compound of Formula(VIII):

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; s is 2; and n is 0, 1, 2, or
 3. 100. A compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein R^(X) is selectedfrom the group consisting of halo, —OH, —OR^(Q1), and substituted orunsubstituted alkyl, wherein R^(Q1) is substituted or unsubstitutedalkyl; R^(Y) is halo or substituted or unsubstituted alkyl; or R^(Y) andR^(X) may join together with the intervening atoms to form a substitutedor unsubstituted carbocyclyl or a substituted or unsubstitutedheterocyclyl; R³ is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁵ is hydrogen or methyl; each instance of R²² isindependently selected from the group consisting of halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA),—OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)R^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; and n is 0, 1, 2, or
 3. 101. A compound of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein

represents a single or double bond, provided if a double bond ispresent, then one of R^(6a) or R^(6b) is absent and R⁵ is absent; R^(X)is selected from the group consisting of halo, —OH, —OR^(Q1), andsubstituted or unsubstituted alkyl, wherein R^(Q1) is substituted orunsubstituted alkyl; R^(Y) is halo or substituted or unsubstitutedalkyl; or R^(Y) and R^(X) may join together with the intervening atomsto form a substituted or unsubstituted carbocyclyl or a substituted orunsubstituted heterocyclyl; R³ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen or methyl; eachinstance of R²² is independently selected from the group consisting ofhalogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA),—OC(═O)R^(GA), —OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂,—SR^(GA), —S(═O)R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),—S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocylyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, wherein each instanceof R^(GA) is independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygenprotecting group when attached to oxygen, and a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted heterocyclyl orheteroaryl ring; each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyselected from the group consisting of hydrogen, halogen, cyano, —NO₂,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1),—C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),—OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),—N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),—N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))S(═O)₂R^(A1),—N(R^(A1))C(═NR^(A1))N(R^(A1))₂, —N(R^(A1))S(═O)₂OR^(A1),—N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)OR^(A1), —SC(═O)_(R) ^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), or—S(═O)₂N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, and asulfur protecting group when attached to sulfur, or two R^(A1) groupsare taken with the intervening atoms to form a substituted orunsubstituted heterocyclic ring; each of R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, halogen,cyano, —NO₂, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, and substituted or unsubstituted alkynyl; orR^(6a) and R^(6b) are joined to form an oxo (═O) group; each of R^(15a),R^(15b), R^(16a), and R^(16b) is independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,—SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3), —C(═O)N(R^(C3))₂,—OC(═O)R^(C3), —OC(═O)OR^(C3), —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3),—OS(═O)₂R^(C3), —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂,—N(R^(C3))C(═O)R^(C3), —N(R^(C3))C(═NR^(C3))R^(C3),—N(R^(C3))C(═O)OR^(C3), —N(R^(C3))C(═O)N(R^(C3))₂,—N(R^(C3))C(═NR^(C3))N(R^(C3))₂, —N(R^(C3))S(═O)₂R^(C3),—N(R^(C3))S(═O)₂OR^(C3), —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3),—SC(═O)OR^(C3), —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),—S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of R^(C3) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, or substituted or unsubstitutedheterocyclyl, an oxygen protecting group when attached to oxygen, anitrogen protecting group when attached to nitrogen, and a sulfurprotecting group when attached to sulfur, or two R^(C3) groups are takenwith the intervening atoms to form a substituted or unsubstitutedheterocyclic ring; R¹⁹ is hydrogen or substituted or unsubstitutedalkyl; q is 2; and n is 0, 1, 2, or
 3. 102. A compound selected from

or a pharmaceutically acceptable salt thereof.
 103. A pharmaceuticalcomposition comprising the compound or pharmaceutically acceptable saltof claim 1, and a pharmaceutically acceptable excipient.